what are newer diagnostic techniques for AD?
PET and functional neuroimaging (FTD)
describe the levels of CSF biomarkers in AD
tau increases by 300%
Ab decreases to about 50% (as there is increased deposition in plaques)
AD is pathologically defined by what?
presence of plaques and tangles
what are beta-amyloid plaques and neurofibrillary tangles?
plaques- insoluble aggregates of b-amyloid proteins that form outside of neurons
tangles- insoluble aggregates of hyperphosphorylated tau proteins that form inside neurons
how do Ab1-42 peptides come about?
b-secretase and y-secretase cleave at their sites on APP leaving a harmful AB1-42 peptide.
what happens to;
APP-null mice
APLP2-null mice
APP/APLP2-null mice
- relatively normal
- relatively normal
- 80% die after 1 week
aggregation of b-amyloid peptide is facilitated by which metals?
zinc and copper
what properties does the Ab1-42 variant have?
- more hydrophobic than Ab1-40
- more prone to fibril formation
- is the predominant isoform found in cerebral plaques
What is the toxic form of Ab-peptide: soluble or insoluble aggregates?
soluble monomeric Ab peptides are toxic to cells in culture and in brains of rhesus monkeys
The evidence for Ab as a cause of AD is (6)
- There is an increased number of plaques in brains of patients with AD
- Genetic mutations in familial (early-onset) AD cause increased production/deposition of Ab peptides (e.g. APP, PS1, PS2).
- Ab plaques appear in Down Syndrome patients (trisomy 21) that carry an extra copy of the APP gene
- APOE4 allele increases the risk of sporadic (late-onset) AD
- Transgenic mice expressing mutant human APP genes develop plaques and neurodegeneration (but not extensive and no tangles)
- Aggregated or fibrillar (but not soluble/monomeric) Ab peptide is toxic to cells in culture and the brains of aged rhesus monkeys.
what do Ab peptides induce?
production of reactive oxygen species, leading to cell damage and apoptosis
Cell culture, clinical and epidemiological studies suggest that what is protective of effects of Ab?
anti-oxidants, Vitamin E and oestrogen
how might Ab peptides act?
as non-selective ion channel or allow release of ROS. Ab may promote the aggregation of tau to form neurofibrillary tangles.
what are the two major hypotheses for AD?
- BAPtists- the accumulation of a fragment of the amyloid precursor protein or APP (the amyloid beta 42 residue fragment or Ab-42) leads to the formation of plaques that some kill neurons.
- TAUists- abnormal phosphorylation of tau proteins makes them “sticky” leading to the break up of microtubules. The resulting loss of axonal transport causes cell death.
where are neurofibrillary tangles expressed and found?
predominantly expressed by neurons in the CNS and predominantly found in axons.
why do NTs interact with tubulin/MTs?
They co-purify with tubulin/MTs, stabilise MTs integrity and promote MT assembly.
where is tau normally/in AD found?
in axons but in AD aggregates and is redistributed to cell bodies and dendrites.
transgenic mice expressing FTDP-17 (disease caused by tau mutations) exhibit what?
Neurofibrillary tangles and neurodegeneration
tau knockout mice exhibit what?
they are normal and show no obvious developmental, cognitive or neuronal polarity defects
together, what do transgenic mice expressing FTDP-17 and tau knockout mice demonstrate?
the presence of abnormal tau/NFTs rather than the loss-of-function contributes to development of AD.
when is tau hyperphosphorylated and by which enzymes?
early in AD- by kinases including GSK3, Cdk5, MAPK, DYRK
what might hyperphosphorylated tau result in?
impair its ability to bind MTs and promotes its aggregation, forming NFTs creating imbalance between kinases and phosphatases and generate excessive NFTs
how might imbalance of kinases/phosphatase activity result in tau hyperphosphorylation and NFTs? (5)
- Association of p25 with Cdk5 leads to activation of Cdk5.
- Activated Cdk5 can inhibit GSK3 by indirect regulation of the inhibitory serine phosphorylation of GSK3.
- Consistently, results and data from studies indicate that Cdk5 acts via protein phosphatases such as PP1 and PP2A, possibly by affecting regulatory subunits.
- GSK3 phosphorylates tau.
- Thus, disruption of inhibitory GSK3 regulation, for example, by altered Cdk5 function, or pharmacological GSK3 inhibitor, like lithium may lead to tau hyperphosphorylation.
what is the importance of tau pathology in AD?
NFTs are common to many forms of dementia and are often the only pathological lesion in these diseases- no conditions where there are plaques only.
NFTs show higher correlation with AD progression than plaques
