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The role of A beta 42 in Alzheimer's disease
1Mayo Clinic Jacksonville, Florida 32224, USA.
Abstract:
Our recent studies of plasma, fibroblasts, transfected cells and transgenic mice show that a fundamental effect of the mutations linked to familial Alzheimer's disease (FAD) is to increase the extracellular concentration of A beta 42. This effect of the FAD-linked mutations is likely to be directly related to the pathogenesis of Alzheimer's disease (AD) because A beta 42 is deposited early and selectively in the senile plaques that are an invariant feature of all forms of AD. Thus our results provide strong evidence that the FAD-linked mutations all cause AD by increasing the extracellular concentration of A beta 42 (43), thereby fostering A beta deposition, and they support the hypothesis that cerebral A beta deposition is an essential early event in the pathogenesis of all forms of AD. Interactions between the basal forebrain cholinergic system and A beta that could influence AD pathogenesis are discussed.
Insights
Familial Alzheimer's disease (FAD) mutations increase extracellular beta-amyloid 42 (A beta 42), a key factor in Alzheimer's disease (AD) pathogenesis. This finding supports the hypothesis that A beta deposition is an early event in all forms of AD.
Area of Science:
- Neuroscience
- Genetics
- Molecular Biology
Background:
- Familial Alzheimer's disease (FAD) is linked to specific genetic mutations.
- Amyloid beta (A beta) deposition in senile plaques is a hallmark of Alzheimer's disease (AD).
Purpose of the Study:
- To investigate the fundamental effect of FAD-linked mutations.
- To determine the relationship between FAD mutations, A beta 42 levels, and AD pathogenesis.
Main Methods:
- Studies conducted on plasma, fibroblasts, transfected cells, and transgenic mice.
- Analysis of extracellular A beta 42 concentrations.
Main Results:
- FAD-linked mutations fundamentally increase extracellular A beta 42 concentration.
- Elevated A beta 42 correlates with early and selective deposition in senile plaques.
- This mechanism is proposed to be directly related to AD pathogenesis.
Conclusions:
- FAD mutations cause AD by increasing extracellular A beta 42, promoting deposition.
- Cerebral A beta deposition is an essential early event in the pathogenesis of all AD forms.
- Potential interactions between the basal forebrain cholinergic system and A beta in AD pathogenesis are discussed.