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- Title
Loss of presenilin function is associated with a selective gain of APP function.
- Authors
Deyts, Carole; Clutter, Mary; Herrera, Stacy; Jovanovic, Natalia; Goddi, Anna; Parent, Angèle T.
- Abstract
Presenilin 1 (PS1) is an essential γ-secretase component, the enzyme responsible for amyloid precursor protein (APP) intramembraneous cleavage. Mutations in PS1 lead to dominant- inheritance of early-onset familial Alzheimer's disease (FAD). Although expression of FAD-linked PS1 mutations enhances toxic Aβ production, the importance of other APP metabolites and γ-secretase substrates in the etiology of the disease has not been confirmed. We report that neurons expressing FAD-linked PS1 variants or functionally deficient PS1 exhibit enhanced axodendritic outgrowth due to increased levels of APP intracellular C-terminal fragment (APP-CTF). APP expression is required for exuberant neurite outgrowth and hippocampal axonal sprouting observed in knock-in mice expressing FAD-linked PS1 mutation. APP-CTF accumulation initiates CREB signaling cascade through an association of APP-CTF with Gas protein. We demonstrate that pathological PS1 loss-of-function impinges on neurite formation through a selective APP gain-of- function that could impact on axodendritic connectivity and contribute to aberrant axonal sprouting observed in AD patients.
- Subjects
GENETICS of Alzheimer's disease; PRESENILINS; NEURAL physiology; AMYLOID beta-protein precursor; NOGO protein
- Publication
eLife, 2016, p1
- ISSN
2050-084X
- Publication type
Article
- DOI
10.7554/eLife.15645