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The effect of FAD-associated mutations in amyloid-beta precursor protein and presenilin-1 genes on Alzheimer’s disease pathogenesis. Zhang, Shuting
Abstract
Pathogenic mutations in amyloid-β precursor protein (APP) and presenilins (PS) genes cause familial Alzheimer’s disease (FAD). FAD is an uncommon form of Alzheimer’s disease (AD) with early onset (before age 65) and a rapid progression but its neuropathology is indistinguishable from the sporadic AD. Amyloid plaque is the unique hallmark of AD, which consists primarily of 40- and 42-residue amyloid β protein (Aβ40 and Aβ42) with the more hydrophobic Aβ42 as its major component. Aβ is derived from APP through sequential cleavages by β-secretase and γ-secretase. According to the “Amyloid hypothesis”, Aβ accumulation initiates the pathogenic cascades leading to AD, including the formation of neurofibrillary tangles, activation of astrocytes and neuronal loss. It has been well established that pathogenic mutations in both APP and PS genes contribute to AD pathogenesis via impaired generation of Aβ. This powerful genetic discovery lends great credence to the “Amyloid hypothesis”, given that APP is the precursor of Aβ and PS acts as the enzyme to generate Aβ. The thorough understanding of the mechanism of these pathogenic mutations could lead to decipher the AD conundrum. Until now, all pathogenic APP mutations are autosomal dominant mutations except for APPA673V. We discovered that APPA673V structurally facilitates β-cleavage at Asp-1 site while inhibited the general APP processing including all α-/β-/γ-cleavages possibly due to the intensified lysosome-dependent degradation. The overall effect of APPA673V on the production of Aβ makes the homozygous state necessary for APPA673V to produce enough Aβ to initiate AD pathogenesis. Mutations in PS genes are another major cause of FAD. As another substrate of γ-secretase apart from APP, Notch plays a fundamental role in neurodevelopment and neurodegeneration. It has been well established that pathogenic PS mutations impaired Notch signaling. PS1ΔS169 is a recently discovered PS1 mutation in a Chinese FAD family. We extensively characterized the function of PS1ΔS169 in mammalian cells and transgenic mice and found that PS1ΔS169 promoted AD pathogenesis via altering γ-cleavage of APP without impairing Notch processing, excluding the contribution of Notch signaling to AD pathogenesis. Our study highlights the possibility of developing specific γ- secretase inhibitors, which may spare Notch signaling in AD therapy.
Item Metadata
Title |
The effect of FAD-associated mutations in amyloid-beta precursor protein and presenilin-1 genes on Alzheimer’s disease pathogenesis.
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Creator | |
Publisher |
University of British Columbia
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Date Issued |
2013
|
Description |
Pathogenic mutations in amyloid-β precursor protein (APP) and presenilins (PS)
genes cause familial Alzheimer’s disease (FAD). FAD is an uncommon form of
Alzheimer’s disease (AD) with early onset (before age 65) and a rapid progression
but its neuropathology is indistinguishable from the sporadic AD. Amyloid plaque
is the unique hallmark of AD, which consists primarily of 40- and 42-residue
amyloid β protein (Aβ40 and Aβ42) with the more hydrophobic Aβ42 as its major
component. Aβ is derived from APP through sequential cleavages by β-secretase
and γ-secretase. According to the “Amyloid hypothesis”, Aβ accumulation
initiates the pathogenic cascades leading to AD, including the formation of
neurofibrillary tangles, activation of astrocytes and neuronal loss. It has been well
established that pathogenic mutations in both APP and PS genes contribute to AD
pathogenesis via impaired generation of Aβ. This powerful genetic discovery
lends great credence to the “Amyloid hypothesis”, given that APP is the precursor
of Aβ and PS acts as the enzyme to generate Aβ. The thorough understanding of
the mechanism of these pathogenic mutations could lead to decipher the AD
conundrum. Until now, all pathogenic APP mutations are autosomal dominant
mutations except for APPA673V. We discovered that APPA673V structurally
facilitates β-cleavage at Asp-1 site while inhibited the general APP processing
including all α-/β-/γ-cleavages possibly due to the intensified lysosome-dependent
degradation. The overall effect of APPA673V on the production of Aβ makes the
homozygous state necessary for APPA673V to produce enough Aβ to initiate AD
pathogenesis. Mutations in PS genes are another major cause of FAD. As another
substrate of γ-secretase apart from APP, Notch plays a fundamental role in
neurodevelopment and neurodegeneration. It has been well established that
pathogenic PS mutations impaired Notch signaling. PS1ΔS169 is a recently
discovered PS1 mutation in a Chinese FAD family. We extensively characterized
the function of PS1ΔS169 in mammalian cells and transgenic mice and found that
PS1ΔS169 promoted AD pathogenesis via altering γ-cleavage of APP without
impairing Notch processing, excluding the contribution of Notch signaling to AD
pathogenesis. Our study highlights the possibility of developing specific γ-
secretase inhibitors, which may spare Notch signaling in AD therapy.
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Genre | |
Type | |
Language |
eng
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Date Available |
2014-02-28
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Provider |
Vancouver : University of British Columbia Library
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Rights |
Attribution-NonCommercial-NoDerivatives 4.0 International
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DOI |
10.14288/1.0074224
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URI | |
Degree | |
Program | |
Affiliation | |
Degree Grantor |
University of British Columbia
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Graduation Date |
2013-11
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Campus | |
Scholarly Level |
Graduate
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Rights URI | |
Aggregated Source Repository |
DSpace
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Rights
Attribution-NonCommercial-NoDerivatives 4.0 International