AD Other Lecturer Flashcards
The healthy brain
Healthy neurones, synapses, glial cells, vascular system
AD stages
Brain changes start decades before symptoms show (up to 15 years)
Amnestic MCI: memory problems, cognitive ok, brain compensates for changes
Cognitive decline accelerated after AD diagnosis (few years)
Total loss of independent function
Pathological hallmarks of AD
Extracellular:
amyloid plaques (blood vessel walls, cerebral amyloid angiopathology) AB
Intracellular:
Neurofibrillary tangles TAU
What is happening during MCI and early AD
Lag of 15 years before prevalence of AD (observation)
Extensive synapse loss in early AD - 44% dentate gyrus
55% CA1
(highly correlated with cognitive impairment)
Hypothetical time course of AD events
Amyloid-beta accumulation
Synaptic dysfunction
Tau mediated neuronal injury (but could this be before synaptic dysfunction)
Brain structure loss
Cognition loss
Clinical function loss
Amyloids
Proteins that can misfold, aggregate and may be insoluble
How are amyloids formed
Processing of amyloid precursor protein - Function in body unknown
APP beta cleavage, transmembrane protein (AB), gamma secretase cuts within plasma membrane leaving just AB and AICD fragment
APP alpha cleavage, cleaves in between AB so prevents AB formation
Could gamma secratase be a target for therapeutics?
Yes
If prevent from working then the formation of AB prevented as cannot separate to for AB and AICD
Presenilins (PS1) mutations (part of gamma secratase complex) found in AD disease
How can targeting alpha cleavage be used for therapeutics in AD
(ADD EXTRA READING)
Increase alpha cleavage
Genetic components of AD
Mutations found in APP and PS1 resulting in increased [AB] in brain (will get AD)
Initial focus on plaques but now on soluble forms of AB
> 50 mutations in APP gene that lead to early onset AD and related to beta cleavage and gamma cleavage (correlation)
Higher prevalence of AD in people with Down syndrome
Copy of chromosome 21
APP found in chromosome 21
Bigger dose of APP so increased AB formation
Woman with partial chromosome 21 copy - did not develop AD and lived til 78 because did not have part of chromosome that holds APP
Mutation in APP protecting against AD and age related cognitive decline
APP mutation A637T
1795 sample - 1 in 100 had the mutation
>80% with mutation protected from cognitive decline
Hek cells transferred with different variants of APP gene, critical comparison - A673T had significantly less AB (causation)
What percentage of cases of AD do not have clear genetic cause?
> 95%
Alzheimer’s disease risk factors
Age
Lifestyle (diet, cardiovascular health, social factors)
Clinical (high blood pressure, diabetes, depression, Down syndrome)
Genetic (APOE variants)
Mutations (APP in familial AD)
preclinical trajectory in AD
Teens and 20s - pre- MCI so preventative action
MCI - modifying
AD - symptomatic
Using MMSE score
Active immunotherapy against AB
Vaccination with AN-1792
Given to moderate to advanced AD
Stopped due to brain inflammation
Research on post mortem brains - plaques were cleared in some but they continued to decline in cognitive ability
Passive immunotherapy
Aducanumab
Given to mild to moderate AD
Slow cognitive decline and dose dependent amyloid removal but not as good as active immunisation
How do we study AD?
Patients brains:
Brain imaging
Pathology
Memory
Mouse models - useful for analysing interactions between AD molecules (cellular mechanisms). No mice model has all mutations/phenotypes and usually mimic familial not sporadic AD
In vitro - cellular mechanisms
Issue with studying AB
Lack of standardisation
AB can oligomerise into many forms
Mice models of AD
Mice expressing mutant APP develop plaques with age
Strong promoter in transgenic mice - Morris water maze platform (spatial memory)
Mutation in APP doesn’t “learn” so still has to search
Assessing basal synaptic transmission in hippocampal slices from mice
Brains of mouse sliced in protective solution and keep alive for a day
Stimulating axons from Ca3 and recoding in ca1 area
Plaques independent disruption of neural circuits in AD mice models
Do neuronal synaptic defects occur before plaques accumulate
Yes
4 months, no plaques, but fewer synapses
2 months, defects in synapse connectivity plaque deposition has not begun
This is for familial AD
How does amyloid beta affect the function of brain cells and their connections?
Amyloid beta is toxic to neurons and synapses (within hours to days in mice)
Cause death of neurones, neurons without tau proteins survive tho
So AB may need tau to cause neuronal death
Causes loss of dendritic spines which impairs synaptic plasticity
AB oligomers decrease dendritic spine density in hippocampal pyramidal neurones
Grew brain slices in organotypic culture
Controlled - good spines
AB monomers - spines still there
AB oligomers - spines lost
Synaptic plasticity
Synapse potentiation
Action potential in presynaptic cell releases glutamate and new synapse respond creating post synaptic potential, passed alone
Threshold so output
Fewer spines and receptors, postsynaptic potentials smaller and more likely to die out
What oligomers of AD do people with symptoms have
Mainly Dimers but also some trimers
aB protein diners impair synaptic plasticity and memory
Tau is required for AB to inhibit synaptic plasticity in hippocampal synapses
Tau knock out mice with AB - did not cause loss of LTP
Seeing electric activity in mice after adding AB and waiting 3 hrs - in humans much slower
Emergence of synaptic and cognitive impairment in mature onset APP mouse model of AD
Transgene of APP in mice which could be switched off by giving oxycyclin in the diet, starts expressing without
Tested mature brain when switched on, 3 weeks, 12 weeks
3 weeks - impaired synaptic plasticity and short term memory issues
12 weeks - impaired plasticity, short term and long term memory issues, plaques
Oxycyclin reintroduced at 3 weeks - return to normal levels
How is AB a driver of AD
Clear genetic link between overproduction of AB and AD
Similar pathological progression of early and late onset AD (LOAD)
aB impair synaptic function in cell culture and mouse models
Will targeting AB cure AD?
Assumption that studying AB will shed light on LOAD
Clinical trials targeting AB reduction have failed so far
AB is not the only driver of AD (eg tau and inflammation)
Tau and amyloid link
Experimental evidence suggests that therapies will have to address both pathologies to be effective
AB can make tau abnormal or tau itself can be abnormal
Mutant APP enhances tangle formation in tau mutant mice
Preventative measures of AD (primary)
Lifestyle changes - diet, exercise etc
Preventative measures of AD (secondary)
Limiting AB or tau accumulation
addressing earliest neuronal dysfunction
Complex downstream cascades are engaged by AB oligimers (LTP & LTD)
LTP impairment and LTD facilitation can cause tau hyper phosphorylation
Excitotoxicity
Late phase LTP impairment
Tau reduction prevents AB induced defects in axonal transport (mitochondria)
Impact availability of mitochondria in synapses
Could be cause of synaptic loss and exociticity
AB affects multiple synaptic functions (EXTRA READING)
Glial cells
Glutamate transporters
AMPAR
NMDAR
Post synaptic density - thinned as disease develops
Mice model seeing how long mice survive with different veriants of tau and AB
Mice expressing human APP with familial mutation die young
Lack of tau lengthens their life span
Form of tau that cannot be transported to dendrites also protective
AB causes tau protein redistribution from axons to dendrites and causes excititoxixity
Normally - tau in axon
AB oligomers translocate tau protein to dendrites with fyn kinase
Fyn kinase causes NMDA receptor subunit phosphorylation and cause excitotoxicity
Challenges ahead
AD disease drug targets eg amyloid beta, tau and phosphorylation, glutamate transporters, AMPRs, caspase 3, fyn, NMDARs
BUT Mechanisms normally used by neurons so AD therapies should reestablish balance
Moving from post mortem to living to reduce failure in trials
AB and tau as tools for diagnostics (EXTRA READING)
Spinal tap
AB oligomers in plasma membrane disruption
Form membrane pores and disrupt ca2+ homeostasis
May also bind to membrane receptors eg glutamate, acetylcholine, insulin
Synaptic removal of AMPA receptors in response to AB causes loss of dendritic spines
AB
Calcinerium
AMPAR endocytosis
Spine loss
Mechanisms of synaptic depression overlap with AB mediated synapse loss
Caspase 3 triggers early synaptic dysfunction in vivo
AB
Mitochondrial stress, apoptosis mechanisms
Caspase 3
Calcinerioum
AMPAR endocytosis
Spine loss
