title: Loss of presenilin function is associated with a selective gain of APP function.
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 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.
authors.affiliation: Departments of Neurobiology, The University of Chicago, Chicago, United States.
authors.forename: Carole
authors.initials: C
authors.lastname: Deyts
authors.affiliation: Departments of Neurobiology, The University of Chicago, Chicago, United States.
authors.forename: Mary
authors.initials: M
authors.lastname: Clutter
authors.affiliation: Departments of Neurobiology, The University of Chicago, Chicago, United States.
authors.forename: Stacy
authors.initials: S
authors.lastname: Herrera
authors.affiliation: Departments of Neurobiology, The University of Chicago, Chicago, United States.
authors.forename: Natalia
authors.initials: N
authors.lastname: Jovanovic
authors.affiliation: Departments of Neurobiology, The University of Chicago, Chicago, United States.
authors.forename: Anna
authors.initials: A
authors.lastname: Goddi
authors.affiliation: Departments of Neurobiology, The University of Chicago, Chicago, United States.
authors.forename: Angèle T
authors.identifier: 0000-0001-8686-1175
authors.initials: AT
authors.lastname: Parent
mesh_terms: D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D015870:Gene Expression; D055879:Gene Knock-In Techniques; D006801:Humans; D051379:Mice; D050505:Mutant Proteins / Q000235:genetics* / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism*; D053764:Presenilin-1 / Q000235:genetics* / Q000378:metabolism*
chemical_list: C545487:APP protein, human; D016564:Amyloid beta-Protein Precursor; D050505:Mutant Proteins; C508853:PSEN1 protein, human; D053764:Presenilin-1
keywords: APP; Alzheimer's disease; FAD mouse models; adenyl cyclase signaling; mouse; neurite outgrowth; neuroscience; presenilin