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

  1. Tomas Fanutza
  2. Dolores Del Prete
  3. Michael J Ford
  4. Pablo E Castillo
  5. Luciano D'Adamio  Is a corresponding author
  1. Albert Einstein College of Medicine, United States
  2. MS Bioworks, LLC, United States
Research Article
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Cite this article as: eLife 2015;4:e09743 doi: 10.7554/eLife.09743

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.

Article and author information

Author details

  1. 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.
  2. 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.
  3. Michael J Ford

    MS Bioworks, LLC, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. 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.
  5. 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.

Reviewing Editor

  1. Bart De Strooper, VIB Center for the Biology of Disease, KU Leuven, Belgium

Publication history

  1. Received: June 29, 2015
  2. Accepted: November 8, 2015
  3. Accepted Manuscript published: November 9, 2015 (version 1)
  4. Accepted Manuscript updated: November 10, 2015 (version 2)
  5. Version of Record published: February 3, 2016 (version 3)

Copyright

© 2015, Fanutza et al.

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.

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