Alzheimers disease Flashcards
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What is common amongst all neurodegenerative diseases?
Loss of synaptic signalling at the early stages of disease
What are the major neurotransmitters in the brain?
Glutamate, GABA, ACh, Noadrenaline, dopamine, seratonin
WHat neuronal population is alzheimers associated w/?
Cholinergic neurones
Where are the NTs associated with alzheimers located?
Basal forebrain
What neuronal population is parkinsons associated w/?
Dopaminergic neurones
Where are the NTs associated with parkinsons located?
Substantia nigra
What neuronal population is associated with Huntingtons disease?
Medium spiny GABAergic neurones
Where are the NTs associated with huntingtons disease?
striatum
Alzheimers symptoms?
Gradual degradation of memory, learning ability, reasoning and ability to make judgements
Why are demetia and alzheimers different?
Alzheimers is a specific disease, dementia defines a group of symptoms
Leading cause of dementia in uk?
Alzheimers
Two defining hallmarks of alzheimers disease?
plaques of amyloid beta peptide and neurofibrillary tangles composed of Tau
Where are the plaques of amyloid beta peptide found (cell-related)?
Extracellular
Where are the neurofibrillary tangles composed of Tau found (cell-related)?
Intracellular
What is Tau?
A protein involved in microtubule assembly (part of the cytoskeleton)
What is a currently emerging hallmark of AD?
Inflammation of reactive glia (microglia)
Characteristic of side effect of inflammation of reactive glia (function-related)?
Side effects are both gain of and loss of function
Genetic risk of AD?
Does exist, however not causative
What kind of disease is AD categorised as (genetic/sporadic)?
Sporadic
Biggest risk factor for AD?
Age
Possible allelic risk factor of AD?
ApoE4 Allele
Amount of ApoE4 needed to cause AD risk?
One copy
Causes of early onset AD?
Autosomal dominant mutations in amyloid precursor protein (APP) or presenilin 1&2 (PS1, PS2)
Link between downs patients and AD?
Downs patients present with it at ~40yrs
Possible reason for earlier onset of AD in downs patients?
Gene dosage of APP–> it is on chromosome 21
Why does APP being on chromosome 21 cause ADs onset to be earlier in downs patients?
More APP is made (three copies of gene instead of 2) so more amyloid beta peptide is made
How can GWAS be used to help establish alleles that could be a risk factor?
GWAS people with and without the disease.
See if there is a statistically significant amount of people with/without x allele in the disease group compared to the control group
If there is this allele/absence of may be a risk factor
What does APOE stand for?
Apolipoprotein E
How many major alleles of ApoE are there?
three
Three major alleles of Apo?
ApoE2, ApoE3, ApoE4
Highest ApoE allele combination risk factor (i.e. 2,4 3,3 etc)?
ApoE 4,4
What is gene penetrance?
If a gene is expressed, the phenotype will occur
What is gene penetrance measured in?
%
What is PS1, PS2?
Presenilin 1 and presenilin 2
How many different mutations have been identified in APP?
> 50
What does the A673T mutation in APP do regarding AD?
It protects against it
How many different mutations have been identified on PS1
> 150
How many mutations have been identified on PS2?
13
Role of PS1?
Component of gamma secretase which cleaves/processes APP
What is APP?
A type 1 membrane glycoprotein
What is the major type of mutation that has been identified on PS1?
Missense
What is the alpha secretase pathway of APP cleavage?
APP is cut in the middle of the amyloid beta peptide sequence
What is significant about the alpha secretase pathway of APP cleavage?
As the middle of the amyloid beta peptide sequence is cut, there is no abp therefore no AD
What is the beta secretase pathway of APP cleavage?
APP is cut to the side of the amyloid beta peptide sequence.
SIgnificance of the beta secretase pathway of APP cleavage?
As APP is cut to the side of the amyloid beta peptide sequence, abp can be formed so there is an AD risk
Why is Tau not a cause of AD?
It instead causes frontotemporal dementia and parkinsonism
