Alzheimer's Disease Flashcards
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
Which areas of the brain are involved with AD?
Temporal lobe
Occipital lobe
Frontal lobe
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
Describe a PET scan
Detects metabolically active cells/ brain regions or cerebral blood flow
How can PET be used to differentiate between AD and FTD?
AD; rear brain inactivity
FTD; frontal brain inactivity
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%
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
What are the pathological hallmarks of AD
Beta amyloid plaques; insoluble aggregates of beta amyloid that are extracellular
Neurofibrillary tangles; hyper phosphorylated tau
What is the function of APP?
Cell adhesion, neuritie outgrowth, synaptogenesis, cell survival
APP -/- normal (underweight, decreased locomotor activity, reactive gliosis)
Describe the difference between the alpha secretase and beta secretase APP pathways
Alpha = non-amyloidogenic Beta = amyloidogenic
Describe the aggregation of the beta amyloid plaque
AB monomer Oligomers Fibrils Diffuse plaques Anti-parallel beta sheets - facilitated by zinc and copper
What is the predominant form of AB found in cerebral plaques?
AB42; more hydrophobic, prone to fibril formation
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
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
What does the “protective” APP mutation do in terms of APP cleavage?
Enhancement of alpha secretase cleavage
What does the pathogenic APP mutation do in terms of APP cleavage?
Enhancement of beta cleavage (amyloidogenic)
Increase AB1-42 peptide
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
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
