Neurodegenerative Disease Flashcards
1
Q
Hallmarks of Ageing
A
- genomic instability
- telomere attrition
- epigenetic alteration
- loss of proteostasis
- mitochondrial dsyfunction
- stem cell exhaustion
- cellular senescence
- increase in disorder
- electrical parameters decline in the nervous system
2
Q
Healthy Ageing vs Dementia
A
- in healthy ageing there is little or no neuronal loss but synaptic function changes
- dementia is pathological ageing and neurological death
3
Q
Dementia
A
- progressive loss of cognitive and intellectual functions without impairment of consciousness
- caused by structural brain disease
- AD is a type of dementia
4
Q
Alzheimers
A
- occurs with age
- leads to neuron death and failure of all brain systems
- degeneration of fundamental circuits
- myelin attacking, synapses dissolving, loss of brain volume
5
Q
AD Discovery
A
- Alois Alzheimer
- sectioned a patients brain with symptoms of AD and stained with dyes
- found plaques and tangles in the brain
- ‘strange disease of the cerebral cortex’
6
Q
Disease Pathology
A
- neuronal loss
- synaptic damage
- amyloid plaques: precipitate of fat/cholesterol/amyloid
- neurofibrillary tangles: helix of protein
- not known which is first or how they’re related
- can occur together or singly in types of dementia
- Increased AB production facilitates neurofibrillary tangle formation
o Tangles more present in mice with mutant APP
- Removing tau gene from mice alleviates symptoms of APP overexpression
o Some symptoms caused by AB may be mediated by dysregulation of tau
7
Q
Amyloid Plaques
A
- extracellular
- formed of B-amyloid peptide and APOE
- overproduction of B amyloid is involved in mutation
- start in hippocampus
8
Q
Neurofibrillary Tangles
A
- intracellular (inside cells)
- paired helical filaments
- major component is the protein tau (hyperphosphorylated)
9
Q
Familial AD mutations
A
- cause early onset AD with autosomal-dominant mutation
- 3 genes: APP, PS1, PS2 (amyloid precursor protein and presenilin protein)
- also APOE4 allele: strongeset genetic risk factor for late onset AD
- TREM2 allele is also a risk factor
10
Q
Presenilin
A
- proteases processing B-amyloid protein
- control rate of production of amyloid
11
Q
Formation of AB Peptide
A
- B secretase cleaves APP
- y secretase (PS) cleaves APP
- assembly of AB into fibrils
- a secretease can also cleave
- cleavage in the membrane is a biochemical challenge
- proteases provide special environment to get water into the membrane via a passage and cleave the peptide bond
- lateral movement of the substrate in between the TM domains 6/7 and cleavage
12
Q
Amyloid Precursor Protein
A
- no known function
- no effect in knockout mice
- overproduction = disease
- found on the surface of all neurons cell body
- cleavage releases fragments and one fragment is amyloid B peptide
- AB is soluble but close to the crystal state so easily forms assemblies (seed) that can build into a plaque
- happens constantly but older people have more
- reach a clinical threshold of plaques that is toxic to system (toxicity not understood)
- overproduction of deposited proteins leads to disease
13
Q
Amyloid B
A
- cleavage by B secretase generates N terminus and intramembranous cleavage by y secretase gives C terminus
- a secretase cleavage precludes AB formation
- AB is usually soluble and cleared from the brain constantly
- duplication of the APP gene and missense mutations in the APP gene cause inherited AD
- failure of clearance can also cause disease
eg. missense mutation speeding up AP production - not clear why AB is toxic to neurons/their function (some have AB without disease)
14
Q
What is amyloid?
A
- amyloid state: elongated fibers with spines consisting of many stranded B sheets
- amyloid fibers are unbranched usually extracellular and found in vivo
- insoluble: 2 antiparallel B sheets with cross B fiber diffraction pattern
15
Q
Tau
A
- microtubule associated protein (MAP)
- no confirmed function
- expressed in all neurons
- IDP with alternative splicing at N terminal exons and microtubule repeat domains
- domains bind different molecules suggesting a central role in signaling pathways and cytoskeletal organisation
- hyperphosphorylation of tay leads to microtubule destruction
- abundant neurofibrillary tangles and neurophil threads comprised of pathological tau
16
Q
Tau Effects
A
- in a disease neuron there is a loss of Tau binding with microtubule dissociation
- tau is sequestered in tangles
- neuronal transport loss
- new biochemical profile
17
Q
Tau Mutations
A
- there is a sequence of amino acids in the tau gene which when mutated slightly increase the possibility of phos.
- overproduction of hyperphos. tau triggers pathology
18
Q
Tau Structures
A
- paired helical filament of tau protein
- filaments make up protein inclusions
- ind. tau proteins form C shapes stacking together to form filaments with antiparallel B sheets
- twisting filaments of stacked hyperphos. Tau layers
- core has C structures with antiparallel sheets surrounded by fuzzy coats : core is pathological
19
Q
GWAS for AD
A
- most cases of AD have no familial mutation
- GWAS showed APOE gene variations (cholesterol binding protein) was a risk factor
20
Q
APOE
A
- 4 versions of the APOE allele
- unknown function
- blood soluble
- somehow gets into the brain and forms deposits around plaques
- specific aa polymorphisms
- if you are homozygotic for 4 version increases risk
eg. only 20% of 4/4 carriers are unaffected at 75
21
Q
APOE Pathology
A
- cholesterol core surrounded by APOE protein of different varieties
- AB is somehow associated with APOE: seeds plaques
- not known why APOE is disease associated
- monomers of AB form oligomers and nucleate insoluble seeds
- fibrils and APOE form amyloid plaques
22
Q
TREM2
A
- mutation increased risk of dementia
- associated in plaques with APOE
- loss of TREM2 function increases amyloid seeding but reduces plaque associated APOE
23
Q
Microglia
A
- macrophage immune cell
- resident macrophages in the brain provide defense
- help with synaptic pruning, neuronal plasticity, phagocytosis, programmed cell death
- can be pathologically over-activated and cause neuro-inflammation
- causes excessive synaptic pruning/inflammation
o TREM2: subjects with one copy of a specific variant have higher AD risk
o TREM2 is expressed in immune cells like brain microglia that clear damaged cells (stimulate phagocytosis and suppress inflammation)
o CD33 is a antigen inhibiting microglia uptake of AB and CD33 mutant mice have reduced plaque levels
24
Q
TREM2 and microglia
A
- TREM2 is a regulator of microglia functions upon AD associated neuroinflammation
- TREM2 is on the surface of microglia
- microglia have a receptor for amyloid/cholesterol to surround plaques
- TREM2 binds cholesterol/AB is a sensor for microglia to detect amyloid plaques
- TREM2 overexpression causes dense core plaque and knockout causes filamentous plaque
25
Q
AD Hypothesis
A
- unknown trigger causes inflammatory shell ausing microglia to overact/digest neurons axons
- triggers increased Tau phos./APP production (these are the agents of pathology)
- aberrant processing of APP forms plaques
26
Q
Other Factors
A
- age, genetics
- vasculature
- innate immunity
- microbiome
- more
27
Q
Sleep and Wake Cycles
A
- AB increases in wake and decreases in sleep
- cerebrospinal fluid analyzed for AB
- soluble AB 1-42 builds up during day (maybe seeding more amyloid plaques) and sleep removes it
- more hyperphos. Tau fragments after sleep restriction
- sleep drives metabolite clearance from the brain
28
Q
Sleep Experiments
A
- blood capillary has extracellular space between glia feet and capillary surface
- space increases during sleep as glial cells (astrocytes) contract
- waste fluid flows down outside of vessels with flow increasing during NREM sleep
29
Q
Therapies
A
- no effective current treatments
- acetylcholinesterase inhibitors and NMDA receptor antagonists increase cognitive performance transiently
- AD develops 10-20 years prior to recognizable clinical signs so by the time it is recognized there are substantial symptoms
- eventually clinical threshold is reached
30
Q
Aducanumab
A
- monoclonal antibodies binding to amyloid fragments and clearing the brain
- controversial and not recommended for approval due to side effects
- clinical trials showed danger to patients
- ideally want a biomarker screen for Tau/AB to take treatment for delaying onset
- want early intervention treatment
31
Q
Development of AD Agents
A
- secretase inhibitors: inhibit AB production
- amyloid lowering antibodies: reduce amyloid burden
- neurotrophic molecules: promote neuron survival
- anti inflammatory drugs: brain inflammation reduced
- phosphorylation inhibitors: tau hyperphosphorylation
- nuclear hormone receptor modulators
32
Q
Origins of Parkinsons’ Disease
A
- some genetic causes: a-synuclein, GBA, LRRK2
- juvenile onset: detects in mitochondrial repair
- toxic environment: insecticides, drugs
- idiopathic: unknown cause
33
Q
Dopamine
A
- neuromodulators
- vulnerable to degeneration in PD
- loss of dopamine signaling in the brain causes severe motor symptoms
- only dopamine neurons die in the disease
34
Q
Dopamine Production
A
- L-DOPA: synthesized from L-tyrosine by tyrosine hydroxylase (expressed in substantia nigra)
- Dopamine: synthesized from L-DOPA by DOPA decarboxylase (found in brain)
35
Q
Dopamine Neurons
A
- found in the substantia nigra and ventral tegmental area
- neurons send axons into all brain releasing dopamine nonspecifically from varicosities
- dopamine influences domain of brain circuitry
36
Q
Volume Transmission
A
- broadcast transmission affecting lots of neurons simultaneously
- G1-5 GPCR: excite/inhibit AC triggered by dopamine
- second messenger affected by dopamine
- affects long term plasticity of gene expression
- changes potassium leak channel opening/closing
37
Q
Dopamine Pathways
A
- control flow of blood through the brain: oxygen supply to circuits in brain based on activity
- motor control: plans and executes actions
- behavioural control
- dopamine is the motivational chemical working on glutamate synapses to modulate excitability
- shortage causes inability to initiate movement
38
Q
L-DOPA Treatment
A
- temporary treatment
- rescues Parkinson rabbits
39
Q
Neural Enzembles
A
- a thought is a neural group firing together from overlapping cells
40
Q
Dopamine Hypothesis
A
- dopamine hypothesis
- membrane resting potential can slightly oscillate
- at -65 there is a higher likelihood of being depolarisation by neighbour
- dopamine via G protein dephosphorylate leak K channels and depolarize the membrane by a few mV
- dopamine can arrange for a neural group to toggle more towards being depolarized : higher probability of the group activating together and initiating a movement
- without dopamine we can’t initiate anything/no neural ensembles can be selected
41
Q
a-synuclein
A
- found in Lewy bodies (precipitates of insoluble aSYN clusters inside neurons)
- pathology of aSYN originates in a small number of nerve cells and spread in a prion like fashion
- no known function/no specific structure and soluble in all neurons
- certain dominant mutations in SNCA gene cause pathology
- eg. mutations genetically linked to familial autosomal dominant Parkinson’s disease: chromosome duplication raises likelihood
42
Q
Pathological aSYN
A
- conversion of aSYN to toxic structure containing B sheets/cross B structure
- B sheet structure within a stack of polypeptide chains
- in studies of soluble recombinant protein, certain conc. in salt produces precipitates forming fibrils out of solution
- monomers form monomers/oligomers that then can produce toxic oligomers
43
Q
Stages of Pathology
A
- spreading of aSYN inclusions appears in a predictable order of brain locations
- spread throughout brain regions
- non motor systems appear before motor dsyfunction
44
Q
Gut and PD
A
- aSYN deposits could form first in the enteric nervous system then move to the CNS
- large intestine presence of aSYN may be a biomarker
45
Q
Prion
A
- prions that acquire alternative conformations that become self-propogating
- PrPc gene: unknown function. soluble and abundant in neurons
- PrPsc: infectious form of PrP. Can copy itself/turn PrPc into infectious form. Different shape that shuts down protein synthesis
46
Q
Prion Fold
A
- prions are defined as alternatively folded highly stable propagating protein conformers
- normal PrPc has a helices (3) while PrPsc has B sheets
(catalytic conversion) - toxic form is not fibrils - is soluble
- toxic prions have B sheets but not insoluble fibrils
47
Q
Unifying mechanism of Neurodegeneration
A
- proteins like pTau/aSYN involved in neuro diseases are prion like
- depending on the prion type the spread is different
- different ‘strains’ of proteins like tau or syn lead to different pathologies
- each prion like precipitate causes selective vulnerability of neural populations
- predictable spread in PD and AD
- transfer mechanism not known yet
- therapeutic possibilities
48
Q
Alzheimer’s AB prions
A
- artificial amyloid fragments injected into mouse predisposed to plaques (overproduction)
- plaques then spread from injection point through the brain (prion like)
- hypothesis of plaques spreading across synapses
49
Q
AB seeds in growth hormone vials
A
- growth deficient kids given growth hormone from pituitary glands of others
- some developed early onset dementia
- misfolded peptide is stable and can be transferred to new patients
50
Q
Prion Fold
A
- novel folds = novel pathology
- stereotype B sheet but different
- disease specific folds in ordered cores of filaments
- diagnostic capabilities
51
Q
Protein Synthesis
A
- unfolded protein response in neurodegenerative disorders
- therapeutic modulation of the PERK pathway
- PERK and other pathways are protective responses of the cell
- cells can detect misfolded proteins in the ER
- PERK kinase autophosphorylates to phos. eLF2: less amenable to helping ribosome translate
- prion activates the pathway and shuts down the synthesis of proteins : toxic to cells
- administering a drug inhibiting the misfolded protein response via PERK inhibition allowed more neurons to survive with higher prion loads but with severe side effects
52
Q
Parkinson’s Causes
A
- Familial mutation provokes aggregation or over production provokes aggregation
- Dopamine neurons not the first to have Lewy bodies but are the most vulnerable
- a- synuclein spreads from neuron to neuron: endogenous synuclein recruited between neurons (pathogenic protein spread)
