Alzheimer's Disease Flashcards by Joanna Mitchell

What is dementia?

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

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Which areas of the brain are involved with AD?

Temporal lobe
Occipital lobe
Frontal lobe

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How is AD diagnosed clinically?

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

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Describe a PET scan

Detects metabolically active cells/ brain regions or cerebral blood flow

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

AD; rear brain inactivity

FTD; frontal brain inactivity

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Can CSF biomarkers be used to diagnose AD?

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%

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Describe the link between hippocampal volume/ cingulum bundle and AD

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

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What are the pathological hallmarks of AD

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

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What is the function of APP?

Cell adhesion, neuritie outgrowth, synaptogenesis, cell survival

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

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

Alpha = non-amyloidogenic
Beta = amyloidogenic

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Describe the aggregation of the beta amyloid plaque

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

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

AB42; more hydrophobic, prone to fibril formation

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

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

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Is AD inheritable?

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

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

Enhancement of alpha secretase cleavage

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

Enhancement of beta cleavage (amyloidogenic)

Increase AB1-42 peptide

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

Gamma secretase

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

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

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

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

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

What is the toxicity of AB?

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

What are the 2 major hypotheses for AD?

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

What are neurofibrillary tangles?

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

Where is tau usually found?

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

Is there any genetic evidence of tau toxicity in AD?

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

What is the impact of hyperphosphorylated tau in AD?

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

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

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

What is the importance of tau pathology in AD?

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

What is the relationship between plaques and tangles?

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

What is the current theory of AD pathogenesis?

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

Describe the multifactorial threshold model

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

Describe the role ApoE in AD

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

Which isoform of ApoE is implicated in AD?

E4 allele

Describe the implication of ApoE4 in AD

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

Describe how ApoE4 acts to progress AD

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

What is the role of the RAGE receptor?

Mediates influx of AB peptide across the BBB

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

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

What are the 3 main targets for treatment in AD?

Production of APP Plaque build up APP clearance

How can AB production be reduced?

Inhibit gamma and beta secretase | Stimulate alpha secretase

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

Cu and Zn enhance peptide configuration | Inhibition of these elements will prevent sticking together

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

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

Describe the model of immunotherapy for removal of AB peptides

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

Describe the use of antibody aducanumab in reduction of AB plaques

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

Can AB plaques be broken apart by ultrasound?

Trial showed that ultrasound treatment can decrease the burden of amyloid plaque This has since been reputed in further trials

What does a good model of AD need to show?

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