Intro Flashcards
When was dementia clinically recognised and by who and how?
It was recognised as a medical term in 1797 by Philippe Pinel when we realised memory loss and physiological confusion across patients.
How did Alzheimers disease become identified, when and by who?
In 1906 by Alzheimer when he had a women patient that had symptoms of short-term amnesia, memory loss, disorientation and dysphasia (impairment in speech).
After her death, he monitored the brain and found pathological changes in the brain which he termed plaques and tangles, along side an enhanced neuroinflammation.
These were within the cerebral cortex.
However, it only became termed Alzheimers by his collaborateor Kraepelin.
What is the cerebral cortex important for?
memory, language, judegemnt, thinking
What are the prevalence statistics of AD?
~500,000 in UK
60% of cases
reach 1.1 million by 2030
1.6 million by 2050
List the modifiable and non-modifiable risk factors of AD.
Modifiable - diet, educatonal level, social interaction, comorbidities, physical exercise
Non-modifiable - genetics, age, sex
How can diets be a risk factor? How have they shown this?
They have monitored mediterranean diets or groups of poplethat have a high intake of vitamen E and C and monitored their association with developnent of AD.
They found that these diets had a reduced risk of developing AD – perhaps due to antioxidants egffects.
How might education cause a greater cognitive reserve?
It is thought that the higher education will result in a brain that has greater neuronal synaptoc strength with strong connections.
How can type 2 diabetes increase the risk of developing AD?
It can by 50%
insulin and AB compete for use of insulin degrading enzyme - this is an enzyme that can work to degrade AB which therefore will end up in the accumulation in the brain.
Increased formation of advanced glycosylation end products which increase neuronal damage upon action on their receptors.
How can sports cause increases risk of AD?
becuae it causes tramatic brain injury which will cause an increase in pathological functions in the brain.
Havign apoe4 is thought to enhance this risk.
What does dichotomous disease mean?
This means there are two forms of the disease.
What are the two types of AD and how arer they characterised?
Familial - less dominent form, highly genetic background, early onset, mutations in PSEN and APP
Sporadic - more dominent, late onset, combination of genetic and environmental factors
What is mendelian inhertance?
This refers to how the genes have been passed through a damily based on the laws of Mendel.
It means that gene inherited from either parent segregates into gametes at an equal frequency.
What does autosomal dominent mean?
Autosomal dominant traits pass from one parent onto their child. Autosomal recessive traits pass from both parents onto their child.
Hardy and Higgons are big players how and why?
In 1991, Hardy’s team uncovered the first mutation directly implicated in Alzheimer’s disease leading to the formulation of the highly influential ‘amyloid-cascade’ hypothesis.
Higgons also involved in devlopment on this hypotheiss.
What is APP and what mutations were found?
Amyloid precursor prtoesin that is found on chromosome 21
Dutch - Frangionne
London - first link to AD - Goate 1991
and more
This tends to clustres in regions of the gene which cause enhanced cleavage and production of long fibrillogenic forms.
What is PSEN and what mutations were found?
PSEN is the presenelin protein which are subunits of the gamma-secretase enzyme.
Several mutations have been found which tend to involve a loss of function gamma secretase, impairing the cleavage of APP and therefore, promotirng abnormal AB secretion
What are GWAS? What have they found?
This is an approach used to find genetic mutations in diseased patients. THey use the full genome of humans and search for small variations called single nucleotide polymorphims
This SNP is when one nucleotide in the DNA chain is swapped for another, thereby affecting transcription and normal activity of the protein.
For SAD, they have foound APOE. complement receptor 1. clusterin, PICALM.
What is APOE and what are the different alleles?
APOE is a gene which generates apolipoprotein E which is a glycoprtoein that is involved in transport of choleterol trhough the CNS. It is generally produced by immine cells. It has also been found to bind to AB and promote its transport around the brain, while regulating metabolidm and clearance.
It has been found to have 3 major alleles which are basically three different mutated forms of the gene and involve residues 112 ans 158.
e4 is the biggest risk and increases it by 40fold with one copy and 10-fold with two copies.
What is the allelic ratio?
The likelihood that the allele will occur, calculated by creating a ratio of the area under the curve for the allele and the wild-type gene.
What is trem2?
A gene that is a transmembrane lipoptotein sensor that is largely involved in the regulation of microglia. It forms a receptor-signalling complex with TYROBO.
What mutations in trem2 have been found?
missense mutation (where the change un nuelcotide will change the amino acid) which loses regulation of microglia and increases neurodegeneration.
What are the statistics with age risk factor?
Why is it thougt this occurs?
1 in 14 over 65
1 in 6 over 80
Age related changes in the brain –> atrophy, inflammation, vasculat damage, oxidative stress
Why might oestrogen be protective for females? How did they determine this?
strogen affects cholesterol and lipid transport, and in the brain, estrogen regulates the expression of low-density lipoprotein receptor-related protein, which has been implicated in Aβ processin
It also binds to its ERalpha/beta recpetors which can be found on glial cells, specifically microglia and promote their regulation.
In some sutdies its effect have promoted normal regulation of microglia, preventing its effect on oxidative stess and preventing acitvation of receptors by AB.
What do the genetic studies show for sex differences?
They show differences in neuroinflammatory pathways, synaptic function and apoptosis.
How? ,.
If some sutdies show a reduction in risk of developing AD with NSAIDs/HRT why hasnt it been approved?
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.
What is the general progression of AD?
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.
What neuropsychological tests are commonly used to diagnose AD?
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
For diagnosis what do PET and MRI and fMRI scans look for?
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
What is the cholinergic hypothesis?
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.
What are the functions of
hippocampus
neocortex
amygdala
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
What is the amyloid hypothesis?
Who generated this and why?
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.
How did Kidd and Terry characterise amyloid and tau? What did they show?
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.
Glennor and Wong are referenced alot, what did they do?
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
How was APP discovered?
What is its structure?
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
Why is down syndrome patients relevant for AD research?
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.
What are the two pathways of APP proteolysis and how do they work?
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
How is the (non)amyloidogenic pathway controlled?
Can be controlled trhough neuronal activity such as acetylcholine causing enhanced activation of alpha-secretease.
Who found the structure of amyloid beta?
What is it like?
Glenner and Wong in 1984
38-43 amino acids in length, ab40 most common, ab42 most pathogenic
What are the structural differences of AB40 and AB42?
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.
What is primary and secondary nucleation?
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.
How can plaques undergo cycles of dissociation and reassociation? What causes this?
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
How are AB monomers protective?
How have they shown this?
- 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
Define an oligomer.
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.
What toxic effects can soluble oligomers have?
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.
Describe protofibrils.
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.
What is meant by fibrils forming in a concentration-dependent manner?
Studies have suggested that fibrils will begin to form only after they have reached a certain concentration within the brain.
Describe fibrils.
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
What pathological features has fibrils been shown to have?
Co-localised with disrupted neurites, regionsof decreased spine density, neuronal loss, nueorindlammation and neurodegeneration.
Describe plaques.
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
In Fig 1.3, what is ADAM9,10,17, BACE, nicastribn, PEN2, APH-1?
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.
What is the structure shon in Fig 1.3A?
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.
What does this chain show in 1.3B?
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.
What are alpha helix
beta sheets
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.
What is a primary protein sequence?
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
What are amino acids?
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.
How is the primary sequency made?
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.
What is prion like seeding?
used to descrube molecular events that share similarities with infectious cycle of prion proteins.
This is where it self-aggregates and spreads between cells
How is AB transported across the brain?
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
What receptors are involved in passing the BBB and what is the route that they take?
recpeotrs for advanced glycation end-products – blood to brain
low-density lipoprotein recpeotr-related protein 1 – brain to blood
What are:
axons
axon transport
intraluminal vesicles
exosomes
intracellular space
extracellular space
interstitial fluid
extrastitial fluid
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 –>
What are methods for ab clearance from the brain?
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.
What is bulk flow?
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.
How is AB spread throughout the brain according to Thal
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
What is the function of
allocortical regions
midbrain regions
diencephalic nuclei
striatum
basal ganglia
basal forebrian
brainstem
cerebellum
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
How did the study of Thal 2002 sicover these finfings?
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
Why is it thought that oligomers are the most neurotoxic forms of amyloid beta?
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.
What are the functions of protein recpetors like p75 neurotrophin, LRP1, cellular prion protein, metabotropic glutamate receptors, alpha subunit containing nicotinic acetylcholine receptor, NMDA receptor, beta2 AR, etx.?
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
What types of glutamate, GABA and acetylcholine receptors can you have?
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
What is the GluN2B subunit?
type of subunit for NMDA
thought to play a role in synaptic plasticity and cognitive function
What happens at low concentration of AB on NMDA receptors?
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
What happens at high concentrations of AB on NMDA receptors?
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
How can tauopathy contribute to excitotoxicity?
Tay interacts with Fyn kinase, which forms a complex with PSD95 and the NMDA recpetor which will be activated by AB
What else can contribute to AB-induced excitotocivity?
Ab acting on presynaptic acetylcholine receptors which will increase intracellular calcium levels and promote flutamate release.
Why would there be these differences on NMDA receptors depending on the concentration of AB?
compensatory function followed by termianl detrimental decline
What is the effect of AB on AMPA recpetors?
reduce AMPA recpetor expression through an increase in degradation and ubiquitnation
or by increasing tau hyperphosphorylation which diminises AMPA signalling
Effects of AB on alpha7nAChR?
endocytosis of NMDA recpetors
increased AB-induced tau photphosryltion through extracellular signal related kilase and Jun0Nterminal kinase pathways
Effects of AB on b2AR?
increased calcium signalling and hyperactivity
promotes tauopathy
How does AB increase tauopathy?
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
How can AB increase oxidative stress?
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.
How can AB cause mitochondrial dysfunction?
APP can act on mitochondiral membrane to blockt ranslocation
AB activates cell death pathways through mitochondrial dission proteins
What is the function of mitochondria?
Why is it bad when they are dysfunctional?
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
What are microtubules?
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
What is the normal function of tau protein?
It is a microtubule stabilisation protein that lines the microtubules by having double rings around them.
What is the struucture of tau?
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
What are the phosphorylation sites?
How does this happen?
What are examples?
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
What happens when tau is hyperphosphorylated?
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
How is tau spread throughout the brain?
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
How is tau secreted?
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
How is pathogenic tau internalised?
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
How is the spread of tau throughout AD characterised?
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.
What are the pathological effects of tauopathy?
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
What are
transentorhinal cortex
entorhinal cortex
limbin alloctotex
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
What is the adaptive immune function like in AD?
adaptive - occurs as response to the disease
increase of T cells which interact with microglia and AB
What are microglia?
resident phagocyte in the CNS that shares properties with peripheral macrophages and monocytes
What is reactive gliosis and what does it involve?
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
What happens when microglia are activated?
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.
What are
cytokines
chemokines
proteases
acute phase reactants
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
What are the different types of activated microglia?
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.
What is the role of oligodendrocytes in AD?
general function –> glia cells that create myelin sheath around neuron axons
in AD –> they become damaged through AB or NFTs,
What receptors are present on microglia?
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
What are the examples of the mediators released from activated microglia?
CD36, IL1, TNFa, IL6
through activation of signalling cascades which promote NFkB transcription of genes
What is the protective function of microglia?
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
What is
phagocytosis
autophagy
pinocysosis
recpeotr-mediate endocytosis
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
What is the bad function of microglia?
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
What are exosomes
extracellular vesicles
How does noradrenaline effect cx3cr1 and amyloid pathology?
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
What are astrocytes?
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
What did the work of Cajal show?
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.
What are the two different types of astrocytes and what are their characteristics?
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
What is
white
grey matter
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
What is gliotransmission?
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
What are some roles of astrocytes?
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
What happens when astrocytes acquire their activated form?
neurotoxic A1 –> neurodegeneration
neuroprotective A2 –> protect environment by promoting clearance, BBB repair, neuronal growth and synaptic resoration
How do astrocytes become activated?
Through micorglia-asotrcyte connection
Release of tnf-a, il1a and c1q activates astrocytes through nfkb signalling pathway causing upregulation of proinflammatory genes
What happens to astrocytes in AD?
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
