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Increased amyloid-beta42(43) in brains of mice expressing mutant presenilin 1.
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Presenilin gain of function causes early onset autosomal dominant Alzheimer disease.
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Inconsistent(4)
Description: Mutations in the genes encoding amyloid-beta precursor protein (APP), presenilin 1 (PS1) and presenilin 2 (PS2) are known to cause early-onset, autosomal dominant Alzheimer disease. The presenilin mutations probably cause Alzheimer disease through a gain of deleterious function that increases the amount of A beta42(43) in the brain.
Experimental Approach:
Pathogenic Narrative Tags:
Inconsistent statements
Three PS1 mutations (L113P, G183V, and insR352) have been identified in families with FTD, a common neurodegenerative dementia that lacks amyloid pathology, implying that these PS1 mutations may confer a stronger loss of function than those causing familial AD, equivalent to high doses of γ-secretase inhibitor.
Shen J
Kelleher R
FAD-linked PS mutations are likely to be genetically antimorphic, causing an intrinsic loss of function as well as a gain of negative function, thereby bringing about an overall loss of PS activity.
Shen J
Kelleher R
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Of the major cleavages of APP mediated by γ-secretase, PS mutations typically increase the production of Aβ42 (and Aβ43), but can impair the normally predominant γ-cleavage following Aβ residue 40 and the more distal ‘‘ε-cleavage’’ following residue 49, resulting in significantly reduced generation of Aβ40 and AICD, respectively.
Shen J
Kelleher R
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PubMed
Supporting(8)
Genes/Proteins: (3)
