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The effect of FAD-associated mutations in amyloid-beta precursor protein and presenilin-1 genes on Alzheimer’s disease pathogenesis.

University of British Columbia

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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2014-02-28

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/44983

Neuroscience

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/