Alzheimer's Disease

Question 1

What is dementia?

Answer 1

Irreversible progressive brain disease that slowly destroys memory and cognitive skills
Affects comprehension, calculation, learning, language, judgement, personality, mood, behaviour and motivation

Does not affect consciousness

Life expectancy after AD diagnosis is around 7 years

Question 2

Which areas of the brain are involved with AD?

Answer 2

Temporal lobe
Occipital lobe
Frontal lobe

Question 3

How is AD diagnosed clinically?

Answer 3

A sure diagnosis can only be diagnosed post mortem

Diagnostic criteria is designed to detect short term memory loss, difficulties with daily living and changes in personality:
Historical info (timing and severity, onset)
Physical exam; head injury, circulatory problems, stroke
MSE

Supported by imaging

Question 4

Describe a PET scan

Answer 4

Detects metabolically active cells/ brain regions or cerebral blood flow

Question 5

How can PET be used to differentiate between AD and FTD?

Answer 5

AD; rear brain inactivity

FTD; frontal brain inactivity

Question 6

Can CSF biomarkers be used to diagnose AD?

Answer 6

More so in the research aspect
Total tau increases to about 300% (neuronal and axonal degeneration)
AB decreases to about 50% (increased deposition within plaques)
Phosphorylated tau increases (NFT)
Combined the 3 increase sensitivity and specificity to around 90%

Question 7

Describe the link between hippocampal volume/ cingulum bundle and AD

Answer 7

Lower baseline hippocampal volume was assoc with increased mean diffusivity of the connecting hippocampal cingulum bundle (HCB)
HCB diffusivity predicts tau accumulation in amyloid positive individuals
HCB diffusivity predicts memory decline in amyloid positive individuals

Question 8

What are the pathological hallmarks of AD

Answer 8

Beta amyloid plaques; insoluble aggregates of beta amyloid that are extracellular
Neurofibrillary tangles; hyper phosphorylated tau

Question 9

What is the function of APP?

Answer 9

Cell adhesion, neuritie outgrowth, synaptogenesis, cell survival

APP -/- normal (underweight, decreased locomotor activity, reactive gliosis)

Question 10

Describe the difference between the alpha secretase and beta secretase APP pathways

Answer 10

Alpha = non-amyloidogenic
Beta = amyloidogenic

Question 11

Describe the aggregation of the beta amyloid plaque

Answer 11

AB monomer
Oligomers
Fibrils 
Diffuse plaques 
Anti-parallel beta sheets - facilitated by zinc and copper

Question 12

What is the predominant form of AB found in cerebral plaques?

Answer 12

AB42; more hydrophobic, prone to fibril formation

Question 13

What is the significance of the alignment of the sequence of 42 residue peptide plaques?

Answer 13

A-beta-42 preferentially form networks of salt linkages and strong hydrogen bonds between ionized side chains of opposite charge which thus form the observed plaques

Question 14

Is AD inheritable?

Answer 14

Yes; majority are sporadic
Hereditary forms of AD generally induce earlier onset AD
Increased formation of AB plaques
Presenilin 1 and 2

Question 15

What does the “protective” APP mutation do in terms of APP cleavage?

Answer 15

Enhancement of alpha secretase cleavage

Question 16

What does the pathogenic APP mutation do in terms of APP cleavage?

Answer 16

Enhancement of beta cleavage (amyloidogenic)

Increase AB1-42 peptide

Question 17

What key enzyme in APP cleavage are the presenilins part of?

Answer 17

Gamma secretase

Mutations will favour amyloid beta peptide formation; particularly in its toxic form

Question 18

What is the evidence that amyloid beta is a cause for AD?

Answer 18

1. Increase n. of plaques in AD patients
2. Genetic mutation in familial AD which cause an increase in AB peptide production (APP, PS1, PS2)
3. AB plaques appear in DS patients that carry an extra APP gene
4. ApoE4 increases risk of sporadic AD
5. Transgenic mice expressing mutant human APP develop plaques and neurodegeneration
6. Aggregated AB is toxic to cells in culture and brains of aged rhesus monkeys

Question 19

What is a specific example of how soluble oligomers block LTP?

Answer 19

When AB oligomers are added; there is a reduction in EPSP

Question 20

What is the toxicity of AB?

Answer 20

Not understood
AB peptides induce apoptosis in cultured cells and post mortem brain tissue
Ab peptides induce production of ROS, leading to cell damage and apoptosis.
AB can insert into cellular membranes and disrupt cellular integrity and act as a non-selective ion channel, ROS production
AB can promote the aggregation of tau to form neurofibrillary tangles

Question 21

What are the 2 major hypotheses for AD?

Answer 21

AB; accumulation of fragment of APP or Ab-42 leads to formation of plagues and death of neurons

Tau; abnormal phosphorylation of tau makes them “sticky” leading to the break up of microtubules, loss of axonal transport and death

Question 22

What are neurofibrillary tangles?

Answer 22

Hyperphosphorlyated tau
Tau is predominantly expressed by neurons in CNS; in axons
Co-purifies with tubulin to stabilize microtubules, promote microtubule assembly
MT is responsible for transport of molecules e.g. nT receptors within neurons

Question 23

Where is tau usually found?

Answer 23

In axons; but in AD aggregates it is redistributed to cell bodies and dendrites

Question 24

Is there any genetic evidence of tau toxicity in AD?

Answer 24

Human FTDP-17 caused by mutations in tau
These mutations have reduced ability to bind, stabilize and promote assembly of MTs
Transgenic expressing FTDP-17 have NFT and neurodegeneration
Tau -/- mice are normal and show no obvious developmental, cognitive or neuronal polarity defects

Therefore, it is the presence of abnormal tau/ NFTs rather than loss-of-function contributed to the development of AD

Question 25

What is the impact of hyperphosphorylated tau in AD?

Answer 25

Tau is hyperphosphorlyated by kinases such as GSK3, Cdk5, MAPK and DYRK)
This impairs its ability to bind to MTs and promotes its aggregation, forming NFTs

Question 26

In terms of tau; could an imbalance of kinases/ phosphatase activity lead to AD?

Answer 26

Association of p25 with Cdk5 leads to an activation of Cdk5. Activated Cdk5 can inhibit GSK3 (which phosphorylates tau)
Disruption of inhibitory CSK3 regulation altered by Cdk5 function may lead to tau hyperphosphorylation

Question 27

What is the importance of tau pathology in AD?

Answer 27

NFTs are common to many dementias
NFTs show higher correlation with AD progression than plaques
Familial AD is due to mutations in APP processing molecules; results in higher levels of plaques and tangles

Ab injection into brains of transgenic mutant tau mice accelerates tau formation

Tau causes epigenetic changes (this can be reversed by blocking of tau) such as chromatic rearrangement
Tau impairs neural circuits; suppression of activity and silencing of neurons

Question 28

What is the relationship between plaques and tangles?

Answer 28

Increased AB leads to increased tau phosphorylation resulting in synaptic loss and cell loss

Question 29

What is the current theory of AD pathogenesis?

Answer 29

Protein accumulation; plaques and tangles
Inflammation; unregulated activation of glia
Lipid distribution; lipid membrane site of APP cleavage

Question 30

Describe the multifactorial threshold model

Answer 30

Many common alleles with a low penetrance
Risk alleles are additive (multiplicative)
Many additive environmental factors
Genes + environment = liability

Liability threshold = disease process

Question 31

Describe the role ApoE in AD

Answer 31

Produced in high levels in liver and astrocytes in brain
Present in lipoprotein particles in CNS which are HDL-like
Binds to soluble and aggregated AB - plays a role in AB metabolism

Exists in 3 common isoforms; E2, E3 and E4

Question 32

Which isoform of ApoE is implicated in AD?

Answer 32

E4 allele

Question 33

Describe the implication of ApoE4 in AD

Answer 33

Presence of ApoE4 allele triples the risk of developing AD and decreases the onset by a decade

Presence of ApoE4 allele is not necessary/ sufficient for development of AD = risk factor

Specific to dentate gyrus of hippocampus

Influences production/ clearance, calcium homeostasis or apoptosis

Regulates membrane cholesterol levels by ApoE and influences AB production

Question 34

Describe how ApoE4 acts to progress AD

Answer 34

Regulates the membrane cholesterol level which has a knock on effect on AB production

Influences AB clearance i.e. ApoE and LRP transports AB peptide across the BBB

Question 35

What is the role of the RAGE receptor?

Answer 35

Mediates influx of AB peptide across the BBB

Question 36

What 2 major proteases are involved with the degradation of AB?

Answer 36

IDE
NEP
Inactivating mutations of IDE and NEP have been detected in AD pts

IDE is mostly cytoplasmic, NPE is a transmembrane protein whose catalytic site is located in its extracellular domain

Question 37

What are the 3 main targets for treatment in AD?

Answer 37

Production of APP
Plaque build up
APP clearance

Question 38

How can AB production be reduced?

Answer 38

Inhibit gamma and beta secretase

Stimulate alpha secretase

Question 39

Describe how copper and zinc inhibition via an antibiotic can prevent AB aggregation?

Answer 39

Cu and Zn enhance peptide configuration

Inhibition of these elements will prevent sticking together

Question 40

How can AB clearance/ degradation be targeted as a model for AD treatment?

Answer 40

Molecules can bind to AB within the brain to facilitate efflux into the periphery for destruction
Inhibition of RAGE receptor

Question 41

Describe the model of immunotherapy for removal of AB peptides

Answer 41

AB injected into individuals to produce antibodies

The plaques formed in brain would be broken down and dispersed by either microglia or antibodies binding themselves

Question 42

Describe the use of antibody aducanumab in reduction of AB plaques

Answer 42

Human monoclonal antibody that reacts specifically with soluble oligomer ABs
There was amyloid plaque reduction that was assoc with an improvement in cognition (MMSE)
There was brain penetration, plaque binding and plaque reduction in transgenic mice

Question 43

Can AB plaques be broken apart by ultrasound?

Answer 43

Trial showed that ultrasound treatment can decrease the burden of amyloid plaque

This has since been reputed in further trials

Question 44

What does a good model of AD need to show?

Answer 44

Face validity; plaques and tangles, cognitive deficits and neurodegeneration

Reliability/ reproducibility; be able to observed consistently in same animals

Construct validity; observed in different environments, in different tests measuring the same things AND across species

Predictive validity; show temporal relevance to the disease and it needs to show that treatment aimed at the insult will make it better