APP and APLP2 interact with the synaptic release machinery and facilitate transmitter release at hippocampal synapses

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Abstract

The Amyloid precursor protein (APP), whose mutations cause familial Alzheimer's disease, interacts with the synaptic release machinery suggesting a role in neurotransmission. Here we mapped this interaction to the NH₂-terminal region of the APP intracellular domain. A peptide encompassing this binding domain -named JCasp- is naturally produced by a γ-secretase/caspase double-cut of APP. JCasp interferes with the APP-presynaptic proteins interaction and, if linked to a cell-penetrating peptide, reduces glutamate release in acute hippocampal slices from wild-type but not APP deficient mice, indicating that JCasp inhibits APP function. The APP-like protein-2 (APLP2) also binds the synaptic release machinery. Deletion of APP and APLP2 produces synaptic deficits similar to those caused by JCasp. Our data support the notion that APP and APLP2 facilitate transmitter release, likely through the interaction with the neurotransmitter release machinery. Given the link of APP to Alzheimer's disease, alterations of this synaptic role of APP could contribute to dementia.

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Tomas Fanutza

Department of Microbiology and Immunology, Albert Einstein College of Medicine, New York, United States

Competing interests
The authors declare that no competing interests exist.
Dolores Del Prete

Department of Microbiology and Immunology, Albert Einstein College of Medicine, New York, United States

Competing interests
The authors declare that no competing interests exist.
Michael J Ford

MS Bioworks, LLC, Ann Arbor, United States

Competing interests
The authors declare that no competing interests exist.
Pablo E Castillo

Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, New York, United States

Competing interests
The authors declare that no competing interests exist.
Luciano D'Adamio

Department of Microbiology and Immunology, Albert Einstein College of Medicine, New York, United States

For correspondence
luciano.dadamio@einstein.yu.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) at the Albert Einstein College of Medicine in animal protocol number 20130509. All surgery was performed under sodium pentobarbital anesthesia, and every effort was made to minimize suffering.

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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.