AD Other Lecturer

Question 1

The healthy brain

Answer 1

Healthy neurones, synapses, glial cells, vascular system

Question 2

AD stages

Answer 2

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

Question 3

Pathological hallmarks of AD

Answer 3

Extracellular:
amyloid plaques (blood vessel walls, cerebral amyloid angiopathology) AB

Intracellular:
Neurofibrillary tangles TAU

Question 4

What is happening during MCI and early AD

Answer 4

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)

Question 5

Hypothetical time course of AD events

Answer 5

Amyloid-beta accumulation
Synaptic dysfunction
Tau mediated neuronal injury (but could this be before synaptic dysfunction)
Brain structure loss
Cognition loss
Clinical function loss

Question 6

Amyloids

Answer 6

Proteins that can misfold, aggregate and may be insoluble

Question 7

How are amyloids formed

Answer 7

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

Question 8

Could gamma secratase be a target for therapeutics?

Answer 8

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

Question 9

How can targeting alpha cleavage be used for therapeutics in AD
(ADD EXTRA READING)

Answer 9

Increase alpha cleavage

Question 10

Genetic components of AD

Answer 10

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)

Question 11

Higher prevalence of AD in people with Down syndrome

Answer 11

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

Question 12

Mutation in APP protecting against AD and age related cognitive decline

Answer 12

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)

Question 13

What percentage of cases of AD do not have clear genetic cause?

Answer 13

> 95%

Question 14

Alzheimer’s disease risk factors

Answer 14

Age
Lifestyle (diet, cardiovascular health, social factors)
Clinical (high blood pressure, diabetes, depression, Down syndrome)
Genetic (APOE variants)
Mutations (APP in familial AD)

Question 15

preclinical trajectory in AD

Answer 15

Teens and 20s - pre- MCI so preventative action
MCI - modifying
AD - symptomatic

Using MMSE score

Question 16

Active immunotherapy against AB

Answer 16

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

Question 17

Passive immunotherapy

Answer 17

Aducanumab
Given to mild to moderate AD
Slow cognitive decline and dose dependent amyloid removal but not as good as active immunisation

Question 18

How do we study AD?

Answer 18

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

Question 19

Issue with studying AB

Answer 19

Lack of standardisation
AB can oligomerise into many forms

Question 20

Mice models of AD

Answer 20

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

Question 21

Assessing basal synaptic transmission in hippocampal slices from mice

Answer 21

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

Question 22

Do neuronal synaptic defects occur before plaques accumulate

Answer 22

Yes
4 months, no plaques, but fewer synapses
2 months, defects in synapse connectivity plaque deposition has not begun

This is for familial AD

Question 23

How does amyloid beta affect the function of brain cells and their connections?

Answer 23

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

Question 24

AB oligomers decrease dendritic spine density in hippocampal pyramidal neurones

Answer 24

Grew brain slices in organotypic culture
Controlled - good spines
AB monomers - spines still there
AB oligomers - spines lost

Question 25

Synaptic plasticity

Answer 25

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

Question 26

What oligomers of AD do people with symptoms have

Answer 26

Mainly Dimers but also some trimers

aB protein diners impair synaptic plasticity and memory

Question 27

Tau is required for AB to inhibit synaptic plasticity in hippocampal synapses

Answer 27

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

Question 28

Emergence of synaptic and cognitive impairment in mature onset APP mouse model of AD

Answer 28

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

Question 29

How is AB a driver of AD

Answer 29

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

Question 30

Will targeting AB cure AD?

Answer 30

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)

Question 31

Tau and amyloid link

Answer 31

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

Question 32

Preventative measures of AD (primary)

Answer 32

Lifestyle changes - diet, exercise etc

Question 33

Preventative measures of AD (secondary)

Answer 33

Limiting AB or tau accumulation
addressing earliest neuronal dysfunction

Question 34

Complex downstream cascades are engaged by AB oligimers (LTP & LTD)

Answer 34

LTP impairment and LTD facilitation can cause tau hyper phosphorylation
Excitotoxicity
Late phase LTP impairment

Question 35

Tau reduction prevents AB induced defects in axonal transport (mitochondria)

Answer 35

Impact availability of mitochondria in synapses
Could be cause of synaptic loss and exociticity

Question 36

AB affects multiple synaptic functions (EXTRA READING)

Answer 36

Glial cells
Glutamate transporters
AMPAR
NMDAR
Post synaptic density - thinned as disease develops

Question 37

Mice model seeing how long mice survive with different veriants of tau and AB

Answer 37

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

Question 38

AB causes tau protein redistribution from axons to dendrites and causes excititoxixity

Answer 38

Normally - tau in axon
AB oligomers translocate tau protein to dendrites with fyn kinase
Fyn kinase causes NMDA receptor subunit phosphorylation and cause excitotoxicity

Question 39

Challenges ahead

Answer 39

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

Question 40

AB and tau as tools for diagnostics (EXTRA READING)

Answer 40

Spinal tap

Question 41

AB oligomers in plasma membrane disruption

Answer 41

Form membrane pores and disrupt ca2+ homeostasis
May also bind to membrane receptors eg glutamate, acetylcholine, insulin

Question 42

Synaptic removal of AMPA receptors in response to AB causes loss of dendritic spines

Answer 42

AB
Calcinerium
AMPAR endocytosis
Spine loss

Mechanisms of synaptic depression overlap with AB mediated synapse loss

Question 43

Caspase 3 triggers early synaptic dysfunction in vivo

Answer 43

AB
Mitochondrial stress, apoptosis mechanisms
Caspase 3
Calcinerioum
AMPAR endocytosis
Spine loss