Tutorial 1: Alzheimer's Disease Flashcards
Describe plaques and tangles.
AD-affected brain regions show a high density of neuritic plaques and neurofibrillary tangles.
PLAQUES: central core of amyloid-B peptide, surrounded by degenerating neuronal processes (positive for Tau protein).
TANGLES: made up of paired helical fragments which consist of abnormally phosphorylated micro tubule-associated tau proteins (p-Tau).
Describe the clinical features of Alzheimer’s disease.
Leading cause of dementia (~50-70%)
Progressive memory loss and decline in cognitive functions
Behavioural and psychological symptoms: agitation, depression, anxiety, delusions
Frequency increases exponentially with age.
Usually onset occurs after 65 years of age.
Death usually occurs 8-10 years after diagnosis.
Gross cortical atrophy in temporal lobe, frontal lobe and parietal lobe.
Synapse loss best correlates with cognitive impairment in AD.
Describe the amyloid cascade hypothesis.
Suggests that the deposition of amyloid-B is the primary event in AD that triggers neuronal dysfunction and death.
Recent studies in mouse models suggest that tau is required for amyloid-B neuronal toxicity.
Lesions containing aggregated p-Tau are found in AD and many other disorders called taupathies (associated with neuro degeneration).
Describe the normal neuronal functions of tau, and list some post translation modifications tau undergoes.
When the phosphorylation state of tau is appropriately controlled, tau binds to micro tubules to regulate their stability and dynamics.
Tau regulates neurite outgrowth and axonal transport.
Phosphorylation is the major post-translational modification of tau. Also undergoes glycosylation, glycation, polyamination.
How is Tau modified in Alzheimer’s disease?
In Alzheimer’s disease, Tau becomes hyperphosphorylated as the result of imbalance in the phosphorylation/dephosphorylation of tau (increase in kinase activity, and decrease in PP2A activity).
Highly phosphorylated tau proteins fall off microtubules and start aggregating, leading to destabilisation of microtubules.
Microtubules destabilisation leads to their dissasembly, causing axonal transport insufficiency.
Unbound tau self-aggregates into oligomers or aggregates. Tau aggregates in axons or dendrites congests axonal transport.
Tau pathology is transmitted synaptically. Interaction between Fyn and Tau induces synaptic dysfunction.
Describe current drugs used for AD.
Current drugs include anti-psychotics and acetylcholinesterase inhibitors to treat the symptoms of Alzheimer’s disease, and have little therapeutic affect.
Describe the new therapeutic strategies being developed to combat AD.
tau and amloid-B-targeted disease-modifying therapeutic approaches are currently being developed.
AB accumulation is mediated by factors including rates of peptide production, aggregation and clearance. potential therapeutic strategies include:
reducing amyloid-B generation by targeting the enzymes that cleave APP (amyloid-B is made from cleavage of APP)
Enhancing, facilitating amyloid-B clearance via activation of amyloid-B degrading enzymes or via passive or active immunisation.
preventing the aggregation of amyloid-beta, and destabilisation of amyloid-beta oligomers.
blocking the interaction of amyloid-B with cell surface receptors
modulating downstream pathways to make the brain more resistant against AB that cannot be removed effectively and safely.
