Intro Flashcards

Question

If some sutdies show a reduction in risk of developing AD with NSAIDs/HRT why hasnt it been approved?

Answer 1

For HRT, early studies illustrated that there was a protective effect of oestrogen. However, later studies were conflicting and actually found that there may be differences on the effect depending on how long they have been using it. For example more recent findings suggest that there actually is an association between prolonged used and increased risk of developing all dementia and AD. While chronic NSAID use has been reportedly preferred over short-term use for prevention of AD [3], one review of both epidemiological and clinical trial studies hypothesizes that such usage might only be beneficial in the very early stages of AD pathogenesis, coincident with initial A-β deposition, microglial activation, and release of pro-inflammatory cytokines. Once the process of A-β deposition has started, NSAIDs are not useful; instead, a detrimental effect can occur owing to their inhibitory activity on already activated microglial cells.

Answer 2

Pathology in the brain can occur 10-20 years before clinical symptoms. Then patients will begin showing deterioration of cognitive functions and show peronsality changes which is when they tend to get diagnosed. Then there is mild where everyday activities are interefered, moderate where nab =y activities are interuppted, and severe strages where most everyday activities are disrupted, before vegetation. Usually ~8.5 yeats but everyone has a different progression.

Answer 3

The Mini Mental State Examination (MMSE) (Folstein 1975) is a 30-question assessment of cognitive function The Addenbrooke’s Cognitive Examination - The Mini-Cog is a two part screening test that is used to assess cognitive impairment (Borson 2000). The Montreal Cognitive Assessment (MOCA) ADAS-Cog

Answer 4

A brain MRI can help doctors look for: brain shrinking (atrophy). damage following a stroke. problems with blood vessels. inflammation. tumours. damage following an injury. In Alzheimer’s disease the hippocampi (circled in the image below) are often affected first. A doctor will use an MRI to see if there are visible changes to these structures, which can help to diagnose Alzheimer’s. PET scans are used to show: abnormal build-up of proteins that cause diseases like Alzheimer’s. how much glucose is present in the brain, to look at brain activity. fMRI not commonly used in humans but can show - increased functional connectivity in early stages which may be a compensatory mechanism dealing with the presence of AB/tau - decreased in clinical stages

Answer 5

That because there is widespread neuronal loss ofin brain regions that have alot of cholinergic neurons, this suggests that the loss of cholinergic signalling is responsible for AD. These brain regions are hippocampus, neocortex and amygdala.

Answer 6

Like many parts of the brain's limbic system, the hippocampus is involved in memory, learning, and emotion. Its largest job is to hold short-term memories and transfer them to long-term storage in our brains for execution of higher-order brain functions t's a major processing center for emotions

Answer 7

That the accumulation of amyloid plaques are responsible for the tauopathy and neuroinglammatory state and neuronal loss throughout AD. This was generated by Hardy and higgins in 1992 because these were the pathology found in the brain several years before diagnosis and the most comoon mutations were surrounging the production of amyloid.

Answer 8

They used electron microsope which uses electrons as illumination source and this allows high resolution images. They done this on biopsy human AD patients. They descriped a detailed struture of plaque sand tangles. NFTs --> many neurons were abnormal containing thick bundles of parallel filaments around the nucleus, some with double helices plaques --> some plaques have central masses of filaents and several types depending on surroundings --> identified amyloid structure they identified that many neurons surrounding plaques contained the PHFs --> therefore suggesting a link between the two identified teh presence of astrocytic processses surrounding plaque.

Answer 9

Major roles in the isolation and identification of the strcture of APP and AB - and some mutations. G & W 1984 - purisfied amyloid beta using chromatography and found its amino acid structure -- suggeted it may be derived from a precursor protein G&W 1984 - isolated the amyloid protein on chromosome 21 and identified it in downs patients Glenner 1979 - investigate cages of amyloid microangiopathy and illustrate that this can reach the brain due to breakdowns in the BBB, also suggest microglia are involved in generation of plaques E&G 1968 - find the structure of amyloid using x-ray diffraction and find the beta pleated sheets formed in an antiparallel nature, transferse to the filament

Answer 10

glycoprotein discovered and sequenced by isolating and purifying the protein from menugeal blood vessels of AD and down syndrome patients It is single membrane spanning domain with large extracellular glycosylated N-terminus and short cytoplasmic C-terminus ranges from 695-770 residues

Answer 11

Down's syndrome is caused by having an extra copy of a particular chromosome, called chromosome 21. One of the known genetic links to younger onset dementia is the amyloid precursor protein (APP) gene, which is found on chromosome 21.

Answer 12

Non-amyloidogenic - APP cleaved by alpha secreatase at site within the AB fragment, releases sAPPalpha and a membrane bound C83 remains Amyloidogenic - APP cleaved by beta-secretase at N-terminus of AB domain, leaving C99 bound to membrane and releases APPsB, gamma-secretase cleaves C99 to generate AB

Answer 13

Can be controlled trhough neuronal activity such as acetylcholine causing enhanced activation of alpha-secretease.

Answer 14

Glenner and Wong in 1984 38-43 amino acids in length, ab40 most common, ab42 most pathogenic

Answer 15

AB40 has an alpha helix structure between res 15 and 36 and a kink before this. Alpha helix is senconday protein structure where the single chain of amino acids is arranged in a coil stabilised by hydrogen bonds. AB42 has a beta hairpin srtucture at residues 31-41. This is two beta strands which is basically a linear chain of the amino acids which have folded over in a pin like structure where hydrogen bonds form between them. This hydrophobic structure promotes the formation of beta-sheets which is the accumulaton of beta-strands in parallel attached by hydrogen bonds. These are hydrophobic structures.

Answer 16

nucleation is usually a term used for biophysics but is not being used to refer to protein due to their stages through different structures. Paimary --> aggregation of two or more AB monomers throug fibril independent pathway Secondary -- aggregation of AB monomers on fibtrils in fibril dependent pathway.

Answer 17

The kinetics at each stage has not been identified, with dissociation of AB42 less due to its hydrophobic nature. Changes in ph and lipid content pH --> low pH decreases dissoation as it promotes stability of N-terminal, high pH thought to promote aggregation lipids --> higher cholersterol promotes reassocaition, other lipids can solubuse AB for dissoaciation

Answer 18

- Synaptic function: study has shown it can act as a protective ligand at a GABAb recpetor to promote synaptic transmission, KO studies shown involvement in synaptic functions and impaired learning ability, - Dissasembly of tau: potential function is disassembling tau dimers by preventing bonds between them - Protection against infection: ab binds to neurotoxins and pathogens, aggregates to plaques to trap the microbes into phagocytes - sealing the BBB - regulate angiogenesis promoting healing of blood vessels to prevent leakage of BBB -- localises around damage regions as a scab/sealant to maintain the integrity

Answer 19

Formed through combination of monomers. Various low and high molecular weight forms and therefore, can be various sizes. It can be soluble or insoluble depending on the secondary prtoein structures. Soluble has no alpha or beta sheet structures. Insoluble has high beta-sheet presence which will be in parallel or anti-parallel structure. This is where the beta strands are atrtached in the same direction or not and tend to be due to stabilitiy and function - antiparalel more stable. Soluble forms can spread throught he brain and insoluble can aggregate further into fibrils.

Answer 20

They can spread throughout the brain and act on various receptors e.g. ach, glutamate, beta2-adrenergic, p75 neurotrophin and prion This can disrupt calcium signalling, mirochondiral function, oxidative dress, tauopathy, synaptic function, neuronal loss, AB aggregation.

Answer 21

One of the intermediate products formed which are large soluble fragments with varied dize. Longer than oligomers but thinner and shorter than fibrils. They also contain beta-sheets. Also have silular neurotoxicity as olligomers, shown to have effects on neuroinflammation through accumulation in astrocytes and microglia.

Answer 22

Studies have suggested that fibrils will begin to form only after they have reached a certain concentration within the brain.

Answer 23

AB monomers or oligomers that have aformed into beta sheets in a parallel nature, with hydrogen bonds for stabilisation. This means that the monomers have formed a secondary protein structure which is hydrophobic. Tgis can progress into a fibril itsellf by formation of more beta sheets or this structure will then aggregate onto an already existing fibtril by attaching through te beta strangs

Answer 24

Co-localised with disrupted neurites, regionsof decreased spine density, neuronal loss, nueorindlammation and neurodegeneration.

Answer 25

Ab fibrils will aggregate together and form insoluble plaques These can be diffuse or dense core or neuritic. Diffuse - no accumulation of glial cells around them Dense/neuritic - compact dense core of AB fibrils surrounded by glial cells, synapse loss and tauopathy

Answer 26

A disintegrin and a metalloprotease 9,10,17 which can all cleave amyloid beta from APP BACE - beta-secrease nicrastin is a regulator of gamma secretase cleavease APH-1 is a component of the gamma srectase complex that regulates its stabilisation PEN-2 is required for endoproteolytic processing of presenilin and conferring gamma-secretase activity to the complex.

Answer 27

This is the cell membrane of a cell where the inside is the cytoplasmin and the structure shows the phospholipid bilayer which acts as a barrier between the external and internal fluid. This is shown because APP is a transmemrbane protein which is sitated on the cell membrane and has some internal and external.

Answer 28

This shows the primary amino acid structure of amyloid beta 42. This is made up of 42 amino acids with their name coded, bound together through peptide bonds.

Answer 29

Secondary protein structure is the repetitive folding of polypeptide chains by hydrogen bonds between the hydroxyl (OH) group and the hydrogen molecule of the adjacent amino acid, leading to the unique shape of the protein. The most common examples are the alpha-helix and beta-pleated sheets. Alpha-helix – a coil formed by hydrogen bonds between the carbonyl group and the amino group of different amino acids. The strong bonds and stability of this structure give it a strong tensile strength, which allows it to form the shape seen in DNA. Beta-pleated sheet – formed by hydrogen bonds between the carboxyl group of one amino acid on one sheet and the hydrogen molecule of an amino acid on another sheet. The sheets can be in parallel or antiparallel.

Answer 30

Primary protein structure is when amino acids bound are together via covalent peptide bonds to form a polypeptide chain. These bonds form between the N terminal and C terminal of amino acids and are highly resistant to heat or chemicals.W

Answer 31

Amino acids are the basic building blocks of proteins. Their structure consists of three main groups as seen in figure 1, namely the amino group or N terminus, the carboxyl group or C terminus, and the R group which contains the functional component of the amino acid. The R group gives the amino acid specific features according to its polarity and charge, which then affect the chemical and biological properties of the protein. There are a total of 21 amino acid types based on their different R groups. 12 of these can be synthesised in the body, while the other 9 must be consumed in the diet and are termed essential amino acids.

Answer 32

Proteins are polypeptide structures that contain chains of AA. The primary is linear chain. Secondary has some regions that are stabilised by hydrogen bonds on polypeptide backbone to create alpha helix and betapleated sheets. Tertiary is based on the interactions of side chains from polypeptide backbone. Primary - each amino acid linked through peptide bonds - rund from N to C terminus - 20 possible amino acids 1) DNA preserves the code to synthesise the proteins - this will be a nucleotide sequence 2) this nucleotide sequence is transcribed into another called an RNA messenger (basically it copies the structrue and allows transfer out of the nuclei). This occurs though help by transcription factors. The intiaition complex recognises the promter region which is usually a concensus sequence. It will then copy from the stard and end codon. 3) after leaving nucleus, a ribosome attaches to begin translation when it reaches the AUG start codon. The ribosome will contain two subunits which doin and bind to tRNA to translate this and identify each amino acid from their codon. Then peptide bonds are formed between each AA. This runs until it reaches the end cogndon UAD.

Answer 33

used to descrube molecular events that share similarities with infectious cycle of prion proteins. This is where it self-aggregates and spreads between cells

Answer 34

Prion like seeding - AB spreads throug neuronal transport from axonally connected brain regions. Here, they will be collected into intraluminal vescile, fuse with PM, rekeased into extracellular space as exosomes Cell-to-cell transport - fiynd in neurons but nothing reported Vascular system - transported across BBB through RAGE and LRP1 recepetors APOE - secreted into ISF by glial cells and interacts with AB which can promote spread and clearance through passing BBB

Answer 35

recpeotrs for advanced glycation end-products -- blood to brain low-density lipoprotein recpeotr-related protein 1 -- brain to blood

Answer 36

axon -> the long projection of a neuron between the cell body and axon terminal that conducts electrical pulses.It is coated in myelin sheath for conduction axon transport --> vesciles are foremed in the cell body and transported by motor proteins along the axon microtubules to presynaptic cites. (kinesin and stenein motors) along the microtubule network. exosomes --> extracellular vesciles that are released from cells upon fusion of multisecivular bodies and the plasma membrane intraluminal vesicles -->

Answer 37

ISF draiginage -> diffusion of AB from ISF to CSF through bulk flow, where it will drain into the blood trhough perivascular arterial spaces proteolytic degradation - degradated by amyloid degrading enzymeas such as insulin degrading enzyme and neprulysin, with the end products being removed by bulk flow or theough blood cell-mediated clrance --> microglia and astrocytes can be involved through phagocytosis and internatlisation for degradation active transport --> transport across the BBB into blood through LRP receptors glymphatic transport --> during sleep there was activation f flial cells that work to increase phagocytosis.

Answer 38

bulk flow is a mechanism where proteins and fluid can travel to and from different cellular compartments due to the presence of a pressure gradient. Therefore, in the brain, ISF can move in a pressure-dependent manner through ISF spaces into ventricular CSF.

Answer 39

Not widely known as ti varied actoss patients and is not as standardised as tau pathology. One study found A 5-phase spread which spreads outwards to inwards. Phase 1 - AB in neocortex phase 2 - spread to allocortical regions phase 3 - midbrain regions including diencephalic nuclei, striatum and basal forebrain phase 4 - brain stem phse 5 - cerebellum

Answer 40

allocortex --> a term used to describe several layers of the cerebral cortex, includes the hippocampus, subiculum, olfactory cortex, entorhinal, retrosplenial and cingulate, the cerebral cortex is divided into allocortex and neocortex, and is the outer layer that lies on top of the cerbum, involved in consiousness, messenger between lobes, and sensory and motor areas midbrain --> connected to brain stem, involved in movement of body dienchepalon --> collection of nuelci deep in the brain including thalamus, hypothalamus, subthalamus, relays sensory and motor information to cerebrum striatum --> nuclei forms part of the basal ganglia, split into ventral (nucleus accumbens and olfactory tubercle_ and forsal (caudate nucleus and putamen), involved in motor and reward basal ganglia --> group of subcortical cuclei including striatum, globus palidus, ventral pallidum, substantia nigra and subthalamic nucleus, involved with morot, cogntion, emotion basal forebrain --> in forebrain below the striatum - include basal ganglia, etx, involved in production of acetylcholine which is then distributed widely throguhout the brain, considered major cholinergic output of CNA brainstem --> region of brain that connects the cerebrum to spinal corte xand cerebellum, contains midbrain, pons and medulla oblongata, regulates breathing, heart rate, coordination, role in sleep cerebellum --> hind brain, motor and balance control

Answer 41

They took brain section from 47 brains from demented and nondemended patients with AD related pathology Used a staining technique and analused distinct regions of AB

Answer 42

Becaue they are soluble which allows them to bind to molecules within the extracellular space such as receptors These receptors include glial cells, lipids, protein recpetors like p75 neurotrophin, LRP1, cellular prion protein, metabotropic glutamate receptors, alpha subunit containing nicotinic acetylcholine receptor, NMDA receptor, beta2 AR, etx.

Answer 43

p75 --> member of TNF family controls survival of neurons as neurotrophin is protective molecule that regulates development and maintenence, but can also contribute to apoptosis programmed cell death LRP1 --> endocytic recpeotr modulate trafficking across BBB, also present on microglia to regulate inglammation CPrp --> antiapoptotic, protection against oxidative stress, regulate trnasnmembrane signalling metabotropic glutamate --> GPCRs that upon binding of ligant can promote signalling pathways, role in synaptic teansmission and LTP

Answer 44

glutamate --> ion channel which allow passing of sodium and calcium AMPA, kainate, NMDA metabotrophic - GPCR GABA --> GABAa --> ligand gated ion channels, allows cholrine flow GABAb --> GPCR which can allow calcium and K flow Ach --> nicotonic - ligand gated ion channel, flow of potassium and sidum M1/3/5 - Gq (PKC) activated GPCR M1 - Gs (cAMP,PKA) activated GPCT M2,4 - Gi activated GPCR

Answer 45

type of subunit for NMDA thought to play a role in synaptic plasticity and cognitive function

Answer 46

Excessive activation of the receptors which prevents synapse generation, promotes neurona death, increased oxidative stress --> damage to lipids, proteins and DNA, promote AB accumulation trhough protelysois of APP

Answer 47

AB depress synaptic activity by supressing synaptic strength through internalisation of glutamate receptors, downregulation of voltage-gated sodium channels and loss of dendritic spines, loss of snaptic inhibition

Answer 48

Tay interacts with Fyn kinase, which forms a complex with PSD95 and the NMDA recpetor which will be activated by AB

Answer 49

Ab acting on presynaptic acetylcholine receptors which will increase intracellular calcium levels and promote flutamate release.

Answer 50

compensatory function followed by termianl detrimental decline

Answer 51

reduce AMPA recpetor expression through an increase in degradation and ubiquitnation or by increasing tau hyperphosphorylation which diminises AMPA signalling

Answer 52

endocytosis of NMDA recpetors increased AB-induced tau photphosryltion through extracellular signal related kilase and Jun0Nterminal kinase pathways

Answer 53

increased calcium signalling and hyperactivity promotes tauopathy

Answer 54

Bind to a2-AR activate glycogen synthase kinase1b and cyclin-dependent kinase 5 which promote hyperphosphorylation of tau. These kinases will also promote aggregation of tau monomers into oligomers. activates caspase-3 which will produce a cleaved tau protein that is aggregative act on cellular prion protein receptor to activate Fyn kinase which will increase another kinase

Answer 55

AB bind to p75 neurotrophin recpetor which activates its death domain and caspases which generate ROS Ros damages proteins which will generate toxic products enhancing oxidative stress.

Answer 56

APP can act on mitochondiral membrane to blockt ranslocation AB activates cell death pathways through mitochondrial dission proteins

Answer 57

is a membrane bround organelle wgicgh is found within cells. Its termed the power house of the cell as it is repsonsible fot using areobic respiration to generate ATP --> oxidative phosphotylation

Answer 58

microtubules are components of cytoskeletin made up of tubulin protein and it continuously undergoes polymerisation and depolymerisation in a hollow tube important for cell motiblity, stability in neurons they can provide a structural backbone for axons and dendrites

Answer 59

It is a microtubule stabilisation protein that lines the microtubules by having double rings around them.

Answer 60

N-terminal projection domain that interacts with other cytoskeletal elements or proteins for signal trasnfuction C-terminal is microtuble binding domain, involved in polymerisation and stabilisation through binding to functional prtoeins like kinases or phosphatases This phorphorylated state is in equalibrium

Answer 61

There is 79 serine or threnonine phosphorlation sites. These are amino acids in the tau primary structure whih most often undergo this post-translational modification. Suggests the primary source of phosphorylation is proline directed SerThr kinase. This is a subclass of protein serine-threonine kinases that phosphorylate proteins on a SERINE or THREONINE residue that is immediately preceding a PROLINE residue. This proline directed protein kinases target the xonsneuss sequence -X-SerThr-Pro-X. T Examples are MAPK and GSK3

Answer 62

Tau loses affinity for the microtubule, the rings begin to disassesmble and it breaks away from the microtuble. Then once in the intracellular space, it begins to aggregate together forming paried helical filaments which aggregate into tangles

Answer 63

transsynaptic spreading --> pathological tau underwent intracellular transmission, involving the secretion and uptake from neighbouring neurons Commonly ptermed the prion like model due to similarity to prion diseases

Answer 64

packaged into microvesicles, internalised by exosomes before the fusion of the vesicle with the plasma membrane in its soluble hyperphosphorylated tau will translocate across the plasma membrane --> unclear full mechanism but perhaps trhough pore like channel structures on the plasma membrane filament actin-containing channels called nanotubes which allow transport without secretion into the extracellular space

Answer 65

receptor-mediated endocytosis bulk endocytosis fluid phase translocation fusion of large containinf cescles with plasma membrane actin-dependent micropinocytosis clatrhin-mediated endocytosis involvement of glial cells

Answer 66

This was characterised by Braak and Braak which processed histological human sections and characterised the pathology into six stages over three units. Stage I-II --> transentorhinal and entorhinal cortex Stage III-IV --> hippocampus, limbic allocortex, neocortex Stage V-VI --> secondary and prunmary fields Therefore, this speads inward to outward.

Answer 67

microtubules breakdown and disupt axonal transport tangles physical obstacle within the axons which prevent transport of vesciles and cargo tangles can sequester remaining functional tau contribute to mitochondiral dysfunction, advance AB formation and disrupt calcium signalling through phosphoryltion of Fyn kinase which forms a complex with PSD95, NMBDA2B and NMDAR --> synaptic disruption, mitochrondiria dysfunction neuroinflammation

Answer 68

trans --> structure in temporal lobe, within entorhinal cortex, involved with episodic memory entorhinal --> in allocortex in temporal lobe and main interface between hppocampus and neocortex, memory, navigation, perception of time limbic allocortex --> regions of the deeper older layers of the cerebral cortex

Answer 69

adaptive - occurs as response to the disease increase of T cells which interact with microglia and AB

Answer 70

resident phagocyte in the CNS that shares properties with peripheral macrophages and monocytes

Answer 71

This is when microglia change chemical and morphology depending on its response to the surrounding environment. Resting --> long processes that extend from small cell body that scan envirnment for foreign insults. Activated --> cell body enlarges and the processes become ramified which are directed towards the foreign body

Answer 72

They migrate to the foeign body through a process dependent on ATP. They initiate an inflammatory response through increased production and relase of inflammatory mediators like cytokines chemokines proteases and acute phase reactants which recruit neightbouring microglia.

Answer 73

cytokines - immune chemical messengers which have various different types to refulate inflammation through telling cells how to behave: cell activation, cell differentiation, cell proliferation chemkines - direct immine cells interferons - initiate defens TNA - regulate inflammation proteases - enzymes which catalyse the cleavage of epeptide bonds, hydrolysis of proteins acute phase reactants - inflammatory markers that mediate indlammatory states

Answer 74

There is M1 proinflammatory or m2 antiinflammatoey and disease associated microglia. Appears like s apectrium rather than being one or the other. DAM is activated in two step process through a trem dependent and trem independent process which enahnces inflammation.

Answer 75

general function --> glia cells that create myelin sheath around neuron axons in AD --> they become damaged through AB or NFTs,

Answer 76

Microglia have cell surface recpetors which are pattern recognition recpetors They include tol like, complement, scavenfer, immunoglobin, major histocompatobilitu class I and class II glycoproteins nad leucocyte common antigens

Answer 77

CD36, IL1, TNFa, IL6 through activation of signalling cascades which promote NFkB transcription of genes

Answer 78

Uses its phagocytic function to internalise and degrade AB for clearance --> adided by AB degrading enzymes and cleared by phagocytosis, autophagy, pinocytosis accumulate around plaques forming a protective barrier to prevent growth

Answer 79

endocytosis is matter that is tkaen into the cells and can be phagocytosis and pinocytosis. entocytosis takes matter by forming a vescle by cell membrane. phagocytosis takes in large matter by forming phagosomes. Only takes in solid particles, merge of lysosomes with phagosome, digestion pino cytosis --> fluids and solules are aken in by a small vescle called a pinosome on the cell membrane,degradation by lysosome receptor-mediated --< the receptors on plasma membrane recognise macromolecules in ECF, which promotes formation of vescle autophagy is clearance of wate from inside the cell - phagosome formed around cytoplasm and organneles, fuse with lysoosme, release of enzymes for regradation

Answer 80

respiratory burst --> generation of superoxide anions which will migrate to insule during phagocutosis which can be realeased into healthy tissue ROS and RNS can activate the inflammasome which can release apoptosis proteins and promote duther AB agrgegation decreased phagocytosis -- down reg of expression of AB receptors and degrating enzymes and upregulation of beta-secretase promote spread of tauopathy thrigh increased tau kinase activity and promoting spread through phagocytosis and exosome secretion

Answer 81

extracellular vesicles

Answer 82

gonzalez-prieto --> noradrenaline increases production of chemokine cx3cl which acts on microglial cx receptor and reduces it sactivation --> contribute to neuronal damage. They analysed microglia in 4xfad mice and found increased cx production and increases action on plaques Li --> found that noradrenaline inhibits microglia dynamics throught he beta-1 adrenergic recpetor, which is impaired in 5xFAD mice due to loss of LC neurons, decreased NA, and activating b2A attntuated amyloid pathlogy

Answer 83

glial cell that forms a tiled organisation throughout the CNS which have a wide variation of functions including immune functions, synaptic pruning, gliotransmission, vasicular control

Answer 84

He worked on astrocytes and made several hypotheses surrounding their role. He believed that they were able to interact with neurons, other flial cells and blood vessels. This was proved by electron microscopy later on.

Answer 85

Protoplasmic --> prominent in grey matter, star-shaped structures with protruding processes that interact with neurons and bloood vessels via end feet Fibrous --> prominent in white matter, elongated, sitated along myelinated axons, interact with nodes of ranvier

Answer 86

both essential parts of brain tissue grey - forms on surface of the brain and in deep grooves, consistents of neurons and allows information processing white - found in deeper tssues and contains nerve fibres covered in myelin, provides communication between grey matter areas

Answer 87

This is a way astrocytes communicate. They are not electrically excitable but can increase intracellular calcium concentrations when communicating to neurons, blood vessels or other glial cells thhrough potassium and sodium channels on their membrane This enahcned calcium levels which can promote release of neuromodulators

Answer 88

Gliotransmission release of neuromodulators contribute to synaptic pruning by guiding migrating axons uptake neurotransmitters through transporters on cell surface control blood flow thrrough release of mediators control nutrient-waste exchange immune function

Answer 89

neurotoxic A1 --> neurodegeneration neuroprotective A2 --> protect environment by promoting clearance, BBB repair, neuronal growth and synaptic resoration

Answer 90

Through micorglia-asotrcyte connection Release of tnf-a, il1a and c1q activates astrocytes through nfkb signalling pathway causing upregulation of proinflammatory genes

Answer 91

Early = reduced synaptic activity, reduced metabolic support, remain protective with protein degradation and antioxidaent defence, phagocytosis Late = advanced microgliosis and AB on astrocytic recpetors activates cellular signalling causing increases in calcium, gliosis, oxidative stress and neuronal death, expression of BACE1, increased AB production, promotion of spread of tauupathy

Answer 92

P2Y1, nicotinic, glutamate metabotropic, RAGE AGE-RAGE, nfkB, P13K-Akt

Answer 93

This is popultoon neuronal activity which represents a cognitive of behavioural state They are dominent at diffferent frequency bands caharacterised on their PSD Several of these brain states can exist at one time across different temporal and spatial scales.

Answer 94

Hans berger first discovered brain states when he used scalp EEG on a monkey and found 8-12 Hz waves which he called alpha wves.

Answer 95

Low = involved across large neuronal space, non-active states, neuronal acitvity suncronised, high ampltidues High = more liocalised in neuronal space, active states, desynchronised activity, small amplitudes

Answer 96

Slow oscillations are slow wave <1Hz and are most commonly found in sleeping states such as NREM. These are osccilations characterised by Steriade and collesgues which have a combination of cycles of up (synch) and down (silence) states. Occur in cerebrl cortex, thalamus, brains te, etc. Involved in sleep dependent memoty consoliaation Formed through recurrent excitation and slow adaptation (dynap depression), or with contributions with inhibitory neurons to control the up/down regulation. Cells involved for up geneation are NDMA, pyramidal for down, GABAa, PV and SST Sleep disturbance found in AD in umans, and decreased dlow wave power during W and NREM in mice

Answer 97

In 1938 by Jasper and colleagues ______ They are waves at 30-80 Hz whcih are fast, local and involved in cognitive functions like attention, memory encoding, object and face recognition and owrking memory. They are present across several brain regions like neocxortex, entorhinal cortex, amygdala, hippocampus, striatum, olfactory bulb, basal forebrain and thalamus.

Answer 98

attention - increased gamma power and coherence during tasks with focussed attention, in human studies EEG show stronger gamma bands in attended visual stimuli than unattended memory encoding - active learning of visual shaped was shown by enhanced gamma power in temporal EEG, increased gamma in MEG in dpatial task, studies where patients memorise sequenceis show increase in gamma object and face recognition - MED study showing pictures of lanporks show increased gamma working memory - two epileptic patients performed wotking memory task and show increased gamma with memory load

Answer 99

The superficial cortical laters and the dendate dyrus This suggested the requriement of inhibitory interneurons

Answer 100

interneurons are neurons found in CNS and act as middle man between efferanad and afferent neurons, allowing communication, these exhibit inhibitory signals for stabulity of the brain PV neurons --> an interneuron subtype that express parvalbumin (calcium binding protein) which can be found as basket cells in amygdala, striatum, cortex and hippocampus, and chandelier cells in cortex chandelier cells - type of GABAergic interneuron which are PV-containing and fast-spiking, they have many branching axons. SST_OLM - OLM neurons are a subset of GABAergic interneurons which will only express SST, will only be found in the hippocampus cholecytokinin basket cells --> subset of GAABergic internueorns found in the cortex and cerebellum, the processes form a backet around cells somas and dendrites PV, SST and CCK are all markers that can be expressed by thes inhibitory neurons which wll alter their function and location. PV --> calcium binding protrein SST --> peptide hormone CCK --> peptide hromone martinotti neurons - dendritic targeting interneurons that project to layer 1 of cerebral cortex, short branching dendrites, can be found in cortex expressing SST

Answer 101

a type of synaptic inhibition where inhibitory signals target the soma of a neuron. it will rlease inhibitroy neurrotrasnnitters which hyperpolarises the neuron, and inhibits it drom gernationg AP. This is done by inhibitoru interneurons such as basket cells and chandelier cells.

Answer 102

montiroing LFP in rat hippocampsus computerational models brain slice xperiments optogenetic experiments

Answer 103

interneuron gamma pyramidal-interneuon gamma inheriting gamma

Answer 104

mutual inhibition between two inhibitory interneurons through GABAarecpetor mediated inhibition which results in strong inhibitory feedback that generates gamma oscillations high firing, low noise --> inhib neurons dire with sharp synchrony irregular noisy -->recurrent synaptoc interactions will overcome asynchrnous allowing generation synchrony occurs when interneuron and partner neuron discharge and have IPSP in synchrnoy

Answer 105

An inhibitory postsynaptic potential (IPSP) is a type of synaptic potential that reduces the action of a postsynaptic neuron. The influx of negatively charged ions causes a transient hyperpolarization of the postsynaptic membrane, driving the neuron away down from the membrane potential, away from the action potential threshold so that it wont fire, resulting in an inhibitory postsynaptic potential (IPSP).

Answer 106

optogenetic experiments showing activation of cortical PV+ GABAergic neurons, but not other subtypes, generated gamma oscillations in vitro show activating metabotropic flutamate receptros result in muttual inhibition between internaurons and generationof gamma oscillation

Answer 107

inhibitory neurons and excitatory pyramdal cells interaction between quick AMPAR excitation and slow GABAaR feedback inhibition through a cyclic behaviour Axon conductuon and synaptic delays cause 5ms phase shift between the spikes which determine the freqyency

Answer 108

Feedback inhibition in neuronal firing by interneurons refers to a regulatory mechanism in which inhibitory interneurons provide inhibitory feedback to modulate the activity of other neurons within a neural circuit. This feedback inhibition plays a crucial role in shaping the dynamics and function of neuronal networks. The process typically involves the following steps: Excitatory input: Neurons within a neural circuit receive excitatory inputs from other neurons or sensory stimuli. Generation of action potentials: Upon receiving excitatory inputs, the postsynaptic neurons may generate action potentials, leading to neuronal activation. Inhibitory feedback: In response to neuronal activation, inhibitory interneurons within the circuit release inhibitory neurotransmitters, such as gamma-aminobutyric acid (GABA), onto the postsynaptic neurons. This inhibitory feedback inhibits further neuronal activity by hyperpolarizing the postsynaptic membrane or shunting excitatory currents, thereby reducing the likelihood of action potential generation. Regulation of network activity: The inhibitory feedback from interneurons helps regulate the overall activity level and excitability of the neural circuit. By providing negative feedback, interneurons can prevent excessive neuronal firing, maintain the balance between excitation and inhibition, and shape the temporal and spatial patterns of neuronal activity within the circuit.

Answer 109

PING c an work withotu ING as removal of II connections in mice did not effect gamma power in ca1 manipulating connection between interneuron and pytamidal cells by knocking down AMPARs reduces the amplotude of gamma

Answer 110

inherited from upstream brain regions occur through phase-phase or phase-amp coupling occurs phase-phase --> faster oscillation couples the several phases of slower rhythm phase-amp --> the amp of faster oscillation is modulated by the phase of slow hythm

Answer 111

Because while they contain populations of excitatory neurons they do not have interaction with inhibitoru interneurons in the ssme manner as PC-PV

Answer 112

sxhizoprenia autism elilepsy AD PD

Answer 113

decline in LTP dysfunction of PC interneurons EEG or MEG have conflucting - some show reduction in gamma power while others show an increased

Answer 114

Differences in experimental conditions - awake/eyes closed, resting, music etx stages of AD varied conrol gtoups - MCI or healthy EEG recording --> combination with TMS may help or compensatory mechanisms

Answer 115

>300 preAD inverted u shape relatinship between AB depositions and gamma band power --> gamma power depends on extend of AD pathology at first at low gamma, gamma increases suggesting compensatory mechanism at high plaques gamma power decreases, suggesting breakdown of neuronal circuits Thougtht to be because AB interfere with PING mechanism

Answer 116

this is where gamma oscillations are modulated by theta oscillatiosn through synchronisatioon or phase locking of gamma oscillations to the phse of theta oscillations This createes a nested organisation, Can occur through cross-frequency coupling like phase-amp, phase-phase, Can be found in hippocampus and neocortex. Involved in memory, attention.

Answer 117

decreased gamma power seen across various animal models in slice experiments and in vivo alterations in activity of inhibitory neurons such as PV, SST, CCSK across hippocampus and PFC thought to be due to vulnerability to AB and tau

Answer 118

Because of difficulties mirroring the disease progression - need for LOAD models.

Answer 119

restoring PV interneurons in hAPP mice improved gamma ang cognition optogenetic activation of PC and SST neurons restored gamma functions like thera-nested gamma induced spike timing optogenetic actvation of PV neuron in 5xfad improved memory retrieval

Answer 120

acetylcholinesterase inhibitors - donepezil, rivastigmine, galantamine NMDA antagonists - memantine In US, china and japan - antibody treatments avaialble which sequester AB

Answer 121

Acetylcholinesterasse is an enzyme involved in the chemical breakdown of acetylcholine These work to prevent this breakdown and promote the extracellular levels of Ach for action on recpetors in order to enhance signalling

Answer 122

First gen (tacrine) was liver toxic Second gen - delayed disease progression by delaying cog decline in ADAS-Cof score by 6-12 months by imrovement of 3-4 oints Donepezil - increase cerrebral blood flow, reduce cortical thinning, astrophy

Answer 123

Some mild side effects which are dose related Patients can be treatment resistent only 60% show a therapeutic response to drugs Very mild effect mild-mod

Answer 124

NMDA receptor anatagonist This works to non competitebely bind to the receptor and block glutamate binding, to reduce glutamate signalling This is done to reduce the exotocic stress found throughout AD and hyperphosphorylation of tau

Answer 125

Significant improvements in cognition and behaviour in moderate-severe patients only Very small effects Commonly prescribed with acetylcholinesterase inhhibtiros

Answer 126

There has been evidence that therre is hyperactivity in preclinical AD which has been shown to modulate AB depositon. Bero 2011 - vibrissal system - show modulation of activity modfulated AB levels Cirrito 2005 - in vivo microdialysis they show AB levels in IDF increase when synaptic activity increased Yuan 2016 - investigate if attentuation of neural acitvity using inhibitroy chemogenetic dreads can reduce plaque pathology. It decreased aggregation, and loss of synaptic loss Yamamoto 2015 - used optogenetic stimulation of ChR2 in APP mice and microdialysis to m onitor change in AB levels. 5 mo chronic opto incrfeased AB burden. Rodriguez 2020 - chemogenetic attentuation of EV hyperactivity reduced AB accumulation and tau spread

Answer 127

Because it can have many functions 1) restore normal neuronal balance which will reduce neuronal damane and promote synaptic plasticity and cognition 2) reduce molecular pathologies 3) improve glia activity

Answer 128

aducanumab - monoclonal antibody that sequesters AB fibrils iv administration 45-60min every 4 weeks lecanemab 0 monoclobal clearing AB iv infusion every 2 weeks

Answer 129

Approved on the FDAs accelerated scheme which means they dont need to finish all phases of a trial before the drug is available with the promise of completeing a recovery trial was because only one subset of patients showed a slight cognitive benefit with many side ffects like oedeme and microheamorrhages in some Also this was completed in early ad so no efficacy or safety data at other disease stages

Answer 130

oxidative stress - antioxidants and vitmin suppkementation (vit E) antispsychotics antibiotics

Answer 131

the manipulation of neuronal ativity to promote or reinstate normal neuronal functionality

Answer 132

deep brain stimulation is where electrodes are chronically implanted into the human brain for delivery of electronic pulses vagus nerve stimulation involves implantation of an electrode into the vagus nerve and supplying electrical stimulation. the vagus nerve is the main nerve of the parasympathetic system (when in resting state) and controls function of various organs.

Answer 133

First done in 1984 but no changes were found. In 2020 stim n hypothalamus reached phase II after reductions in cognitive decline and increased hippocampus volume, but then some pateitns worsened so the trial terminated.

Answer 134

Some improvement in cognitive tests but none approved.

Answer 135

They developed an approach for non-invasive brain stimulation which means the skull does not need opened and instead the electrical current is supplied over the human scalp to result in activation of cortical regions. It resulted in the development of several transcranial brain stimulation methods like TMS, tDCS and tACS

Answer 136

transcranial magnetic stimulation --> delivers rapidly alternating current hrough a coiled wire above human scalp transcranial direct current stimulation --> delivers current through electrodes placed on scalp surface with electrical current penetrating skull completing through anodal and cathodal electrodes. Anodal shifts resting potential towards diring, cathodal hyperpolarises surrounding neurons. transcranial alternating current stimulation --> delivers oscillating current at certain frequency

Answer 137

30 sessions of 20 Hz for 6- weeks improved cognitive score

Answer 138

Improbeent in cognitive tests after treatment for 10 days in AD patients

Answer 139

helathy subjects show improved cognitive funcitons but limited studies in AD patients.

Answer 140

prolonged and enhanced neuronal activity promotes synaptic plasticity through LTP and LTD

Answer 141

ef1alpha - protmotoer expressed in most cell types DIO - double floxed inverted open reading frame -- enables conditional and cell-type specific expression using two loxp sites plaqces inberted orientation flanking the transfene. Then in cre-dependent neurons, this cre recombinase will allow cleavage and expression of the trangene ChETA - modified version of ChR2 have faster knetics and light sensitivity Ai32 - mouse line that contains cre-dependent ChETA

Answer 142

Optogenetic stimulation of PV interneurons in 5xfad mice at 40-Hz using chr2 in ca1 Increased LFP gamma power Reduced AB by 50% increased microglia activation ___________ Anothewr actuvatung medial septum show improved spatial memory _______ Another increase AB pathology --> potentially due to the AB induction mechanism

Answer 143

Because they express channelrhodompson in PV neurons but then oprogenetically stimulatie the basal forebrain PV neurons They do this as these will project to the cortical GABAergic neurons in order to sllow entrainment of upstream regions.

Answer 144

Potentially because gamma oscillations being generated in an alterantive way may ave opposing effects.

Answer 145

TI --> using multiple electrical fields with a frequency in range of neural activity US --> ultrasound waves from coils on brain suface, will vibrate neuronal circuits

Answer 146

transcranial focused ultrasound at 40-Hz targeting hippocampus for 1-h per day for 5-days increased microglia and colocalisation of microglia and AB tACS modulated gamma activity

Answer 147

Rager Singer 1998 - visual light flicker of variable frequency and measured signals by LFP recordings, showed increase in gamma range Herrmann 2001 - clinica trial in humans presented with flickering light and seen increase at 40-Hz Jones 2019 - monitored EEG in humans by 40-hz light flicker, seen increase 40-Hz with more entrainement with eyes open Pastor 2003 - 16 humans EEG, 40-Hz activation of cisual cortex

Answer 148

Optogenetics --> decreased sol/insol AB, increaded microglia RNA phenotype, microglia Acute --> reduction in soluble AB40/42 levles, not insoluble by 50% in virusal cortex and hippocampus, enhanced phagocytic microglia phenotype, reduced phosphorylated tau --> effecrts were transient Chronic --> 1h/7 days --> reduction in plaque load and area in cisual cortex but not somatosensory or hippocampus

Answer 149

They completed genus and showed an improved cognitin

Answer 150

The landmark studies also test other frequencies such as 8, 80 and random and they did not see any other effects. Buszaki paper test 4hz as he sas this is the normla for visual stimulation.

Answer 151

A --> entrainment of gamma in AC and hippocampus, reduced AB and improved behavipour in NOR/NOL, vascular association with AB, vascular dilation, reduced tau phosphorlation, increased microglia and astrocytic repsonse AV --> entrainment in CA1 and PFC, activated cluistering phnepotype of microglia across these regions, reduced AB in mPFC

Answer 152

First clinical trial in humans for sensory stimulus 6 patients with either AD or MCI 10 days of 40Hz light for 2h per day No significant decrease of AB found promted an increasin duration of treatment.

Answer 153

AV stimulation 1h per day at 40 Hz for 4-8 weeks 10 patients with MCI neuronal activity entrained at 40Hz during sessions improved functional connectivity in default mode network after 8-weeks no change in AB athology, tauopathy or immune profiles

Answer 154

AV stimulation 1-h per day 40Hz for 6-months with eyes closed patients with mild to moderate AD improved circadian rhythmicity cognition stable, while control groups declined in scores

Answer 155

The same trial but at different phases. AV stim at 40 Hz for 3-months What patients?? entrained gamma oscilations across multiple regions 0 cortical and hipoicampus decreased ventricular enlargement improved circadian rhythmicity improved functional connectivity of the DMN reduced hippocampal atrophy improvements in face-name associated delayed recall tests no sig changes in cog score tests

Answer 156

a large network of brain regions: mPFC, posterior cingulate cortex, RSC, medial temporal lobe, lateral temproal cortex Supports various brain functions and is active in awake states. abnormalities found in AD

Answer 157

Assessing the safety of the treatment - find good adherance and mild side effects ___

Answer 158

seem to be rare and mild worsening of hearing loss mild dizziness headaches

Answer 159

This is a company made by Tsai and another colleague where they have made a human headset that has headphones and glasses for AV stimulation. They have started a large clinical trial in several hundred mild to moderate AD patients 1h AV tratment for up to 1 year

Answer 160

increased activation of NF-kb pathway within 5-60 mins, MAPK pathway after 60-mins increased gene expression of the proteins involved in these pathways increased expression of NF-kb in neurons, not microglia, thought neuron activity increase, increase calcium, increase activation of neuron nf-kb pathway, increase transcrption and release of cytokines, cytokines acitvate microglia

Answer 161

use their ion buffering functions to regulate ionic flow across cortical layers secodnary-mediated response through action on noradrenaline pathways However, it is not through actuon on GABAergic neurons as a GABA antagonist attentuated the neuronal and microglial effects.

Answer 162

increase activation of the NFkB and MAPK siganllign pathways through phosphorylation of cascade proteins promote transcription of cytokines recruitment anda ctivation f microglia promotion of phagocytosis, clearance of plaques, neurtrophic functions

Answer 163

It promotes vascular dilation and cerebral blood perfusion, promoring AB clearance Some human studies also show a decreased hyperexctiability which will restore EI abalance to prevent synaptic damage and astrophy This can all promote reduction of neirnal loss and promote behaviour imprrovements

Answer 164

low cost easy to implement usef fiently no tissue damage with other neuromodulation approaches

Answer 165

lack of cell-type specificity effects across disease stage, sex differences remain unclear brain wide effects unknown MOA unknown conclicting findings not understoof normal effect on gamma in AD not known effect of enhanced mciroglia unknown

Answer 166

not a full representative of human disease each model has different phenotype powerful for research choose a model suitable for your experiment

Answer 167

rodents - genetic manopuation non human primaes - lemur and various types of monkeys, gorrilas,chimpanzee, show natural generation of AB, some with tau, some with atrophy dogs - show agre dpenedent rise in AB and tau, decline in cognition, inglammatory markers dosophilia - expression of human genes, with APP being same basic structure as human APP, contains all secretases, produces AB fragments, also tragegene can be done using CRISPR zebradish - tau transgenic, show phosphorylation and congormaiton changes of tau, goof for in vivo imaging c-elgans - it contains human ortholog of APP and tau genes so can make transgene stains to produce AB40/42

Answer 168

live human brain tissue IPSCs zebrafish embyros cell based cultures

Answer 169

short lifespan rapid reproduction easily maintained

Answer 170

Trem2 KO mice - mutations associated with LOAD consortium working on development humanised AB, APOEe4, TRem2 mutation incorporated into C57 --> no behavioural phenptypes increased inglammation, no plaques hAB Ki --> agre related increases and impairments

Answer 171

3xTgAD - Oddo - triple transgenic mouse model expressing APP and tau301P trangenes on PSEN1 KI background --> forms amyloid, tauopathy, gluosis, synaptic damage and memory deficits --> limitation is the mutation of tau is not found in AD Tau P301S eTg4510

Answer 172

The promoter ensures the transgene is exressed at the appropriat levels in the relevent cell population

Answer 173

firs establused in 1990s through genetical engunerring where they used trangenesis to express FAD mutations in mice These increased AB and cognitive decline but did not have tauopathy or neurodegeneration Decelopment of models using mutations in PSEN instead but failed to have AB Development of double transgenic mice that coexpress muttations in both APP and PSEN1/2 Have addiditve effects causing enhanced AB formation

Answer 174

genetic engineering techniqie used to introduce foriegn DNA from another species into the genome of an organism. 1) isolate gene of interst 2) construct transfene by adding promoters 3) delivery into organism --> common approach is microinjection into fertilised eggs or embyros 4) integrated into genome 5) PCR 6) breeding

Answer 175

APP not authentic off-taget effects of enhanced APP/AB --> neuronal functions, calciumgomeostasis, transcription specific to FAD

Answer 176

first generation in 1995 by Games APP with Indiana mutation with PDGF-b promoter AB from 6-months in cerebral cortex with spreads wirth gliosis and age synaptic problems at 8-months no tauopathy or neurodegeneration memory loss at 3-months

Answer 177

Hsiao 1996 mutations in APP - swedish under hamster prion promoter plaque and gliosis from 10-months memory impariements - spatial - at 10-months no neuronal loss

Answer 178

Mucke 2000 overexpress APP through swedish and indiania mutation plaques from 5-6 months gliosis form 6-9 months neuronal loss from 30months cognitive decline from 4-months

Answer 179

Because in APP models there is large overexpression of other AB fragments that usually have physiological functions. So overexpression of these could cause impariments.

Answer 180

Radde 2006 APP swedish mutation and PSEN1 without exon 9 plaques from 6-months with gliosis memory impariemtns - spatial - from 5-6 months

Answer 181

Oakley 2006 express 5 FAD mitatuons in APP (swedish, glotida and london) and PSEN1 mutatiosn site directed mutagenesis rapid formation of AB depositions from 2-months with fliosis synaptic degeneration from 4-months neuronal loss from 6-months loss of cholinergic neurons at 6-months 30% less PV cells at 12-months formation of intraneuronal AB memory impairements from 6-months hyperactivity sleep disturbances no tauopathy sex differences

Answer 182

AB continues in males and plaques around 10-months females plaquteu around 14-months oestrogen acting on the oestrogen response element situated on the Thy-1 promoter

Answer 183

Made to overcome limitations of APP overexpression Introduction of humanised AB which contained FAD mutations in APP First was swedish and Beyretuther/iberian mutations generating APPNL-F Increased AB, limited change in APP from 6-months change in synaptic health cognitive decline at 18-months To make more aggresive other mutations have been inroduced

Answer 184

humanised AB is a modified version of AB that has been genetically motifiedd to minimic the human form This was done by changing three amino acids and is now used for animal model generation

Answer 185

An animal model generated by Saido and colleagues. an APP knock in model that contains swedish, iberian and arctic mutations No overexpression of APP, but increased AB production, AB42/40 ratio and aggregation Similar to NL-F but the pathology is accelerated. plaques ~3-months and cognition and spatial deficits ~6-mo

Answer 186

humanised AB ki tau ki APOEe4 Ki

Answer 187

To prevent use of swedish mutation ad it interfers with use fo beta secretase inhibitors Sato developed APPNL-F/PSENP117L

Answer 188

needed aggressive AB load to confirmsystem not investigating pathological contributions so dont need native pattern dont need presence of taupathy quick phenotype

Answer 189

Sectioning of tissue and undergoing iterations of washing and staining with stains or antibodies ebfore mounting sections and imaging with a specific microscope. Pros - easy, cheap, qwuick, reliable Cons - labor intensive, time conduiming, damage to sections, no 3D distbition, single read out

Answer 190

Usually used to samle neurotransmitters etc within the brain ISF. Soluble AB released by neurons into brain ISF - measure of AB metabolism and degradation. A probe contains tubular dialysis membrane which lacks whatever you are trying to measure. Then perfusion begins and the molecule will pass into the tubular probe. Then the probe will be removed and the collected solute will be measured through various techniques like spectrometry. Pros - precice measure, cna be done in vivo, allows repeat measure, long recording times Cons - depletes surrounding area, tissue injury, loe temporal resoliton

Answer 191

Developed a mcriumminoelectrode probe that was coated in AB antibodies to try improbe microdialysis approaches to be quciker This involved amperometry which quantifies the oxidation of tyrosine residue at position 10 on human AB --> level of current reflects AB levels had a loss of sensitivity after 2-h and only able to detect human AB so limited.

Answer 192

Where multiple photons are used at the same time at lower energy to cause the same energy transfer as a single photon. Allows longer wavelengths to be used to allow deeper imaging to occur. It uses pulsed laser to prevent excessve energy use. Pros - high resolution (~1um), longitudinal monitoring of plaques , repeat measures, low bleaching Cons - low temporal resolutin. head-fixed, anaesthetised, inflammaiton, low depth resolution

Answer 193

Single photon single high eneergy, low wavelength for excitation, limited depth, greater photodamage due to higher energy photons Two photon use of two lower energy photons by using two photons at double the wavelength --> generates the same energy, better depth resolution, pulsed laser reduces bleaching

Answer 194

Rigid or flexible small diameter light guice that can be inserted into the brain for light delivery and collection

Answer 195

takesseries of xray scans around the body Pros - hgih reoslution (1mm), low cost, available Cons - low resolution, hard to implement in lab

Answer 196

MRIs employ powerful magnets which produce a strong magnetic field that forces protons in the body to align with that field. Pros - high spatial sres, moderate cost, probes can be stored long termm, repeat measures, Cons - no freely behaving, low temporal resolution

Answer 197

inj of radioactive tracer, pet system monitors the number of photons emitted from the radioactive substance Pros - markers, 3D analysis COns - expensive, low abailaniliy, not accessable, short half life, storage issues, varied results across animal

Answer 198

They worked on developing a 3D scanning approach using large field multifocal ulllumination and optoacoustic tomography Used Ab probe called HS-169 which was injected IV bolus when mice were anaesthetised. Not been shown for use wwith ip inj. LMI allowed measurements of cortical AB deposits but had limited depth, Developed a vMSOT sytstem (volumetric multispectral optoacoustic tomography) for mapping AB across whole brain. This had massive tranduar above head with mulriple points for ultrasound waves to pass as a variton of wavelenght

Answer 199

Chen 2018 - CRANAD-3 - infraref probe but requires specific maging that limits spatial resolutin Yang 2021 - Akalumine - luciferase which is sequestered byy AB to re;ease akalumine creating bioluminescence klunk 2002 - m04 klunk 2004 - benzothiazole amyloid binding agesnts - modified thioflavin T by adding benzothiazoles, allow PET imahing skovronksky 2000 - ratioligand probe called BSB which show affinity to AB after intravascular injections

Answer 200

Developed a new way to monitor AB using bioluminsecence imaging Previosus work done try to insert luciferase into the AB or APP fragement but this alters its functions. They developed Akalumine which is a substrate for luciferse which binds to AB to which will promote the rlease of Akalumine and cause bioluminescence. In normal conditions, Akalumin binds to luviferase to generate bioluminescence which declines rapidly. With AB, Akalumine will be sequestered inside the aggregates and will be slowly released. Therefore, if AB is presenent the bioluminescence should last for longer. They show good binding properties, an enhanced buoluminsecce, and show gewarer intensity in 5xfad mice

Answer 201

production of light by a living thing through chemical reactions in the body, luviferase is an enzyme that catalyses oxidation of luciferin causing it to product a glow

Answer 202

optical method where implanting an optic fibre into the brain and illuminating and collecting emitted fluorescence pros - real time, rapid temporal resolution, access to deep brain regions, awake behaving aniamls, cheap set-up cons - low spatial resolutoon, indflammation

Answer 203

made m04 by removing carboxyl groups. showed staining in post mortem brain slices showed competition goof binding affinity. injected iv and ip and showed comparable staining with topically applied TS

Answer 204

parallel to the AB fibrils but antiparallel to beta sheets required minimum of 5 AB monomers hydrogen bonds formed between positibvely charged amino acid residues on beta sheets and negatively charfed sulfonate groups on CR

Answer 205

H bonds - weak electrostatic attractions between hydrogen atom --> important for stabilisation sulfonate - chemical groups containing sulfur atom bonded to three oxygen atoms and one carbon. Negatively charged, hydrophilic and promote water solubulity hydrophilic - addinity for water, polar, charged, dissolve nitrogen double bone - two paris of electrons shared between two atoms --> stronger and rigid structure sulphonic acid - sulfor atom bonded to three oxygen and one hydrogen. Strong acidic groups, water soluble hydrophobic - repel water, insoluble, nonpolar, aggregate napthales - sulfonic acid groups attached to napthalene ring structure, used in organic synthesis salicylic - phenolic ring, caboxyl acid froup, common rganic product carbon d - two pairs of electrons shared between two carbon atoms --> restricted roataion carboxyl groups - functional groups containing cabonyl (C=O) and hydrocyl group attached to carbon, acific

Answer 206

pros - allows more understanding about AB structure and growth, was used as a derivative to make more dyes cons - low selectivity, had hydrophilic charge which meant it couldnt pass the BBB, large MW

Answer 207

chryamine G Methoxy-x34 Methoxy-x04

Answer 208

Removal of acidic naphtahalensulfonic acid groups repaced with less acidic and more lipophloc sallicyclic hroups Less acific more lipophilic poor optical properties

Answer 209

removal of acidic napthalasulfonic acid groups addition of salicyclic groups replacement of nitrogen double bonds with carbon double bonds reduced molecular weight improved fluorescent properties rediced lupophilic properties limited entry to brain

Answer 210

removal of acific napthasulfonic acid groups addition of salicyclic groups replacement of nitrogen fouble bonds with carbon double bonds removal of carboxylic group reduced molecular wight improved fluorescent properties imrpoeved lipophility

Answer 211

- development, proof of ip and iv administration in vivo condello - injected M04 in vivo and then several days later harvested brain and applied TR to see difference in growth, did up to 90-days and M04 rermained, quantified speed of plaque gwoth Crowe - followed plaque growth over 4-weeks in 5xfad mice hefendehl 2016 - montiroing glutamate dynamics with new sensor around AB in APPPS1 mice using 2PM, show increased glutamate next to plaques , inj 24 before each imaging session hefendehl 2011 - use multiphoton to show AB formation over time in APPPS1 to determine their growth rate, m04 injected before each imaging session, some with GFP under iba1, show longitudainal monitoring jung 2015 - inj 24 before each recording with 2PM in APPPS1 mice to see the accumulation of microglia Mayer - to monitor plaque gworth and the recruitment of microglia, injected with M04 before imaging sessions liu - study effects on microglia on AB in Cx3cr1 mdeficit mice with time lapse imaging using 2Pm, see stable signal of m04 over 90 days

Answer 212

Oros - good BBB permeabiity, administered ip and iv, stably bound, only available COns - overlapping spectra, low wavelength, binding to beta-sheets

Answer 213

first to use fibre photometry for neuroscience stained the neocortex through multi-cell bolus loading of calcium indicator oregan green 488 BAPTA-1 monitored spontaenous calcium trnsients

Answer 214

chemical densing optics

Answer 215

Pros - low cost, commercially avalable, reliable COns - difficult implanting, damage to tissue, one depth

Answer 216

a fibre is placed into two clamps, leaving a centre region free which is the pulling region. This pulling region is heated using a special laser causing the fibre to melt. Upon melting, the clamps begin to move at a specific speed to acquire the desiired taper thickness and angle --> parameters corresponding to higher viscosities (higher VELOCITY and negative DELAY values (continued heating)) produced longer and thinner tapers this creates two TF

Answer 217

pros - better implant, not as inavsive, lowwer inflammation, bettter depth reiltuoon Cons - limited depth resolutiona cross brain, frahile, not much info on analusis

Answer 218

GECI genetically encoded calcium indicators - change fluorescence in response to changes in intracellular calcium senses the change in calcium by a calcium protein can be FRET based and single fluorophore based GEVI genetically encoded voltage indicators - change fluorescence in response to changes in membrane potential across neuronal membrane detects these changes by a voltage sensing domain which can be poteassiu channels or rhodosposns, proton channels FRET or single fluorphore

Answer 219

biocompatibility - not toxic to rodent SNR - detect a strong signal photostability - deterioration of signal excitation/emission spectra - no overlap with other controbutors kinetics - depends on what your sensing expressed

Answer 220

trangenesis -- genetic manipulation by introducing modified gene viral gene derlivery - delivery of packaged virus which contains the sensor in utero electroporation - injected into the ventriles of embyronic brain and then electrical pulses are used to transfer the DNA into cells multicell bolus loading - injectioninto extracellular spcace, diffusion

Answer 221

brain wide expression remains stable iver severla generations varied expression throughout the brain - interfere with region/[athway speciifc experiemnts

Answer 222

region and cell specific manner cellular location synaptic direction difficulty targeting, invasive

Answer 223

brain tissue -- m04 spectra short which will absorbed greater brain depositions exist at this wavelength - lipofuscin emmit at 650 with bandwidth of 100 nm bleaching of tissue FP system -- optic fibres and patch cable have internal reflection conflicting reflectiveindexes cause energy to be released into cladding which transfers to fluorescence recovery over time

Answer 224

the material that is used has greater AF also the melting of the core and cladding may allow molecules in which increases AF

Answer 225

displacement betweern brain tissue and optic fibre movements of patch cable corrected using isospectiv channel

Answer 226

The same way we do by measuring the srea od the light collection prfoile and modelling approach to make it all equal to ~1mWmm2

Answer 227

combination of M04 and FF will allow detection of plaques in vivo to conform this novel approach is feasible to monitor plaques by identifing a positive correlation with histology

Answer 228

that TF photometry allows in vivo real time depth resolved plaque detection to establish a novel protocol for real time in civo plaque accessment across depth by determining optimal light protocols and analytical approaches for using TFs

Answer 229

this approach will allow monitoring of plaque modifications caused by GENUS expose mice to genus and monitor changes in AD pathology by determining the effects on neuronal activity and plaque pathology

Answer 230

dementia is an umbrella term used to describe a set of diseases that have memory loss. There are various types which include AD, PD, vascular dementia, dementia with lewy bodies and frontotermporal dementia, and mixed. AD - cahracterised by AB, tau, memory loss, most common PD - characterised by motor symptoms, loss of dopaminergic neurons in substantia nigra, can occur with dementia VD - impaired blood flow to the brain DLB - characterised by alpha-synucleic in lewy bodies FTD - loss of temporal and frontal lobes, mutations in TDP mixed - mix of different types, like AD anf VD

Answer 231

to review all recent meta analysis studies to show the risk factors of dmentia. - 3 new risk factors: alcohol, TBI and pollution - charactierisated into early, middle and late life risk factors - education earl life as after late adenlecsnce protection not as evident - mid can be heating loss and TBI as these are prevantable with hearing aid and reduced risk of head injuty late can be poluution and smoking - even stopping smoking for 4 years reduced the tisk

Answer 232

selective vulnerability refers to subpopulations of neurons in brain systems that may be more probe to abnromal function or death due to disease. In neurodegenerative diseases it can be complex due to various proteins that can interfere with various types of neurons and brain regions. Neurons in EC and CA1 are vulnerable to decreased oxygen and glucose dlivery. However, most studies have failed to gather a deeper knowledge on this. RNA-seq studies show that in EC excitatory neuron populations were selectively vulnereable, in layer II including pyramidal neurons. they found no evidence for selective vulnerability inhibitibitory neurons in EC.

Answer 233

the entorhinal cortex is one of the first cortical brain regions to exhibit neuronal loss in AD. Particualrly in layer II. This includes principal neurons in layer II. important for memory this will occur with changes in the hippocampus with signs of molecular pathology and selective loss of pyramisal cells in CA1. important for memory This begins to spread to the neocortex effecting temporal a and prefonal lobes. There is loss pyramidal neurons in neocortical regions. regions involved in langiage, reasoning and social behaviour Additionally cholinergic neurons in the basasl forebrain. Primary sensory cortexes are relaitvely resistent to degeneration until late stages.

Answer 234

pyramidal exictatory neurons have been shown to be degenerated in hipocampus, entorhinal cortex and neocortex cholinergic neurons in basal forebrain are early degenerated loss of GABA/glutamatergic due to AB/tau/inglammatory functions

Answer 235

slow (<1), delta (1-4), theta (4-10), alpha (10-15), beta (15-30), gamma (30-90) slow --> involved in sleep and NREM delta --> sleep theta --> occur in REM and when mrunning alpha --> relaxed wakefulness beta --> active wakefulness gamma --> cognitive tasks SWRs --> occur in quiet wake and NREM - memory consol

Answer 236

pyramidal neurons interneurons (PV and SST) glial cells In cortex --> PV basket and chandelier cells, SST martinotti cells In hippo --> PV basket, SST OLM

Answer 237

I think it is an exciting route and it is good news to have a new therapeutic available. I do have concerns that the ffect was only in small groups of people and the effect was miniscule. Also the side effects are large. I think ensuring targeting of AB that doesnt have any beneficial functions is important. Combinational theapy

Answer 238

seen reductions after several hours that was maintained for 24h

Answer 239

Contains a carboxyl group, an amino group and a side chain. They link by joining the amino group with carbocyl group of an adjacent AA. Side chains have different properties - acididc, basic, polar, non-polar

Answer 240

glycine alanine leucine tyrosine serine threnonine gluamine proline glutamate

Answer 241

Transcription --> in the nucleus Translation --> cytoplasm or rough endoplasmic reticulum - in an cell compartment that has ribosomes

Answer 242

RNA polymerase is used to attach to the DNA recognised by the TATA box. This binds to the comnlementary base pairs and attaches them to the template strand - A-T, G-C, C-G, T-U Elongation continues until the end sequence. Then it gors through convertion into mRNA by RNA spicing where introns are removed.

Answer 243

it exits the nucleus and enters the cytoplasm single stranded RNA correlaponding to nucleix acid sequence of gene after protein synthesis - it degreated

Answer 244

it acts on a specific receptor. autocrine --> bind to receptors on same cellt hat released it paracrine --> bind to recpetors on nearby cells endocrine --> bidn to receptors on cells far away

Answer 245

Kastaneka group have worked bu optogenetically stimulating APP/PS1 mice for 1 month at 0.6 Hz hey seen decreased AB at 1.2 they seen increased AB

Answer 246

excitatory post synaptic potential local depolarisation of the postsynaptic membrane action of an excittory neuron on a cell will cause influx of sodium and calcium which increases the membrane potential, brings it to the A threshold, and promotes firing

Answer 247

1) frequency analysis in vat, rabbit and rat and find the 40-Hz activity in all three of these animals 2) writes a book on neural mechanism, EEG and the oscillations found

Answer 248

review paper that charactierses and describes the amyloidogenic pathway, including formation of AB and aggreagtion.

Answer 249

a review that secribes potential rputes for clearance of ab from the brain

Answer 250

A paper where they develop a new tau probe which was approved by FDA for pet scanning

Answer 251

review paper that characterised the progression of neuropathological changes in alzheimers disease including tau, plaques and glia§

Answer 252

a reviw that discusses the interaction between AB and tau and how each of them can promote each others pathology

Answer 253

A review on neuroinglammation and its relationship with amyloid and taus, specific focus on microglia

Answer 254

Review on the role of astrocytes in normal healthy brain and in AD

Answer 255

discussion of brain oscilaltion - particularly slow and gamma - including their generation, loss of function in AD and methods used to improve them.

Answer 256

Review of recent studies on anti-amyloid therapies to summarise and analyse their current clinical power

Answer 257

a review which summarises all animal and human studies that have been completed and discusses potential ways this moa

Answer 258

summarises mouse models of AD and what limitations and pros of each generation there are

Answer 259

a review on the use of fibre photoemtry for neuronal and non neuronal cells overview of the general principle of FP discuss use in multimodal with electrode - show detection of p-waves discuss use for non neuronal cells by detecting calcium transidents in calcium signals

Answer 260

Basket - inhibitory neuron with extensive axonal arborisations which form a basket like structure around the soma of target neurons, they release GABA onto the soma and dendrites of pyramidal neurons causing perisomatic inhibition Chandelier - inhibitroy internueon, a lot of axonal terminals that form cartrides which attach to the axon of pyramidal neurons for perisomatic inihibtion

Answer 261

Cerebrum - split into two hemisphers - have four lobes - frontal (executive functins), parietal (sensory), temporal (audotroy processing), occipital (visual processing) Cerebellum - back of brain - recieves input from cerebral cortex and sends to motor areas of brainstemand cerebrum - motor brainstem - base of brain and contains pons, midbrain, medulla oblongatam - redulation of breathing, sleeping, balance Diencephalon - locaded in deep brain - consiststs of thalamus, hypothealmus - relay station for sensoryinfo, homeostatic functions

Answer 262

The glymphatic system is a waste clearance which involves rasnfer of ISF anf CSF across perivascular spce through aquaporin water channels on glial end feet. The ISF is the fluid that surrounds and bathes brain cells, while CSF is the fluid that circulates around the brain and spinal cord. the perivascular space, which is the space surrounding blood vessels in the brain. Aquaporin-4 (AQP4) water channel protein, which is highly expressed on the surface of astrocytic endfeet in the perivascular space. Robust during sleep, especially during non-rapid eye movement (NREM) sleep. During sleep, the interstitial space in the brain expands, facilitating the flow of CSF and ISF and promoting the clearance of waste products. Xie shows that this effect has a role of promoting clearance of AB during sleep.

Answer 263

In TF we are attempting ato acquire real-time signals over a duration of time. The AF can recover and therefore, over the time of recording will increase. The FF experiments were completed on a short time scale where AF recovery is minimal. Additoonally, the low AF cable and LED and FF have lower AF thatn the TF system that showed AF recovery only over days rather than hours if bleached properly.