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

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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.

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Carole Deyts

Departments of Neurobiology, The University of Chicago, Chicago, United States

Competing interests
The authors declare that no competing interests exist.
Mary Clutter

Departments of Neurobiology, The University of Chicago, Chicago, United States

Competing interests
The authors declare that no competing interests exist.
Stacy Herrera

Departments of Neurobiology, The University of Chicago, Chicago, United States

Competing interests
The authors declare that no competing interests exist.
Natalia Jovanovic

Departments of Neurobiology, The University of Chicago, Chicago, United States

Competing interests
The authors declare that no competing interests exist.
Anna Goddi

Departments of Neurobiology, The University of Chicago, Chicago, United States

Competing interests
The authors declare that no competing interests exist.
Angèle T Parent

Departments of Neurobiology, The University of Chicago, Chicago, United States

For correspondence
aparent@uchicago.edu

Competing interests
The authors declare that no competing interests exist.

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols (#71339) of the University of Chicago. The protocol was approved by the Committee on the Ethics of Animal Experiments of the University of Chicago (Permit Number: A3523-01).

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This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.