Loss of presenilin function is associated with a selective gain of APP function

• Published in: eLife Vol. 5
• Main Authors: Deyts, Carole, Clutter, Mary, Herrera, Stacy, Jovanovic, Natalia, Goddi, Anna, Parent, Angèle T
• Format: Journal Article
• Language: English
• Published: England eLife Science Publications, Ltd 19-05-2016; eLife Sciences Publications Ltd; eLife Sciences Publications, Ltd
• Subjects: adenyl cyclase signaling; Age; Alzheimer's disease; Amyloid beta-protein; Amyloid beta-Protein Precursor - metabolism; Amyloid precursor protein; Animals; APP; Axon sprouting; Axonogenesis; Cyclic AMP response element-binding protein; Etiology; FAD mouse models; Flavin-adenine dinucleotide; Gene Expression; Gene Knock-In Techniques; Gene mutations; Genetic aspects; Health aspects; Heredity; Hippocampus; Humans; Metabolites; Mice; Mutant Proteins - genetics; Mutant Proteins - metabolism; Mutation; Neural networks; neurite outgrowth; Neurons - metabolism; Neuroscience; Neurosciences; Physiology; presenilin; Presenilin 1; Presenilin-1 - genetics; Presenilin-1 - metabolism; Proteins; Secretase; Software; Statistical analysis; APP; mouse; FAD mouse models; neuroscience; presenilin; neurite outgrowth; Alzheimer's disease; adenyl cyclase signaling
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/eLife.15645

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 Gαs 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.