Alzheimer's disease and synaptic dysfunction Flashcards
What are the five ‘A’s of Alzheimer’s disease?
Apraxia - difficulty carrying out motor tasks despite intact motor systems
Agnosia - difficulty identifying objects and faces
Amnesia - a deficit in memory
Aphasia - loss of ability to understand and use language
Associated features - depression, insomnia, wandering, aggression, personality changes
What are the three familial genes associated with alzheimer’s?
APP - mutations in the amyloid precursor protein that result in enhanced beta-amyloidogenic processing
PSEN1 and PSEN2 - mutations in gamma secretase that result in enhanced beta-amyloidogenic processing
These are associated with famililal early onset alzheiemr’s
What genes are associated with late onset alzheimer’s?
APOE gene. This confers a risk factor where APOE2 is protective and APOE4 carries increased risk. The APOE gene is also associated with coronary heart disease and T2D.
It has recently been found that APOE4 increases risk for amyloidogenic processing but also for tau hyperphosphorylation.
What is the canonical wnt signalling pathway?
This is also known as the wnt/b-cathenin pathway
The secreted wnt ligand binds to its receptor frizzled. This causes inhibition of glycogen synthase kinase 3 (GSK-3) mediated phosphorylation. This prevents degradation of β-catenin and hence an increase in gene transcription
It is critical in neurodevelopment, as it is required for correct orientation of neural cells - highly important for forming proper synpases. Many brain regions have highly ordered orientations of neurons, such as in cortex and the hippocampus.
The pathway is also expressed in the mature brain.
How are wnt signalling pathway related to tau pathology?
it results in the inhibition of glycogen-synthase kinase, which results in phosphorylation of tau protein.
How are the wnt signalling pathways related to AB pathology?
wnt signalling activates MAPK and JNK pathways, which promote production of protective sAPPa - involved in non-amyloidogenic preprocessing.
b-cathenin is a downstream molecule of wnt, and interacts with presenelin-1 which is a part of the gamma-secreatase complex.
wnt signalling promotes non-amyloidogenic preprocessing of APP.
What are the limitations of the Wnt cascade hypothesis?
It would not solve one of the greatest issues of tau and amyloid hypotheses of alzheimers, which is the spatio-temporal seperation of tau and amyloid pathology.
What are some functions of Wnt signalling?
Organogenesis
midbrain development
stem cell proliferation
regulates synaptic transmission and plasticity
What are the three reasons that Wnt singalling may confer a therapeutic target for neuroprotection?
(i) they act as potent regulators of hippocampal synapses and impact in learning and memory;
(ii) they regulate adult neurogenesis
(iii) they control AD pathogenesis
What is the wnt Ca2+ pathway?
Wnt/Ca2+ pathway, ligand binding to Fz receptors allows the trimeric G proteins and subsequent activation of phospholipase C (PLC), which increases the production of diacylglycerol (DAG) and inositol triphosphate (IP3), and thus generating an increased intracellular Ca2+ concentration that activates Ca2+-dependent proteins. This includes PKC.
