1. Neuroscience
Download icon

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
  • Cited 41
  • Views 2,012
  • Annotations
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.

Metrics

  • 2,012
    Page views
  • 618
    Downloads
  • 41
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, Scopus, PubMed Central.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Download citations (links to download the citations from this article in formats compatible with various reference manager tools)

Open citations (links to open the citations from this article in various online reference manager services)

  1. Further reading

Further reading

    1. Computational and Systems Biology
    2. Neuroscience
    Brian Q Geuther et al.
    Research Article Updated

    Automated detection of complex animal behaviors remains a challenging problem in neuroscience, particularly for behaviors that consist of disparate sequential motions. Grooming is a prototypical stereotyped behavior that is often used as an endophenotype in psychiatric genetics. Here, we used mouse grooming behavior as an example and developed a general purpose neural network architecture capable of dynamic action detection at human observer-level performance and operating across dozens of mouse strains with high visual diversity. We provide insights into the amount of human annotated training data that are needed to achieve such performance. We surveyed grooming behavior in the open field in 2457 mice across 62 strains, determined its heritable components, conducted GWAS to outline its genetic architecture, and performed PheWAS to link human psychiatric traits through shared underlying genetics. Our general machine learning solution that automatically classifies complex behaviors in large datasets will facilitate systematic studies of behavioral mechanisms.

    1. Immunology and Inflammation
    2. Neuroscience
    Alessio Vittorio Colombo et al.
    Research Article

    Previous studies have identified a crucial role of the gut microbiome in modifying Alzheimer’s disease (AD) progression. However, the mechanisms of microbiome–brain interaction in AD were so far unknown. Here, we identify microbiota-derived short chain fatty acids (SCFA) as microbial metabolites which promote Aβ deposition. Germ-free (GF) AD mice exhibit a substantially reduced Aβ plaque load and markedly reduced SCFA plasma concentrations; conversely, SCFA supplementation to GF AD mice increased the Aβ plaque load to levels of conventionally colonized (specific pathogen-free [SPF]) animals and SCFA supplementation to SPF mice even further exacerbated plaque load. This was accompanied by the pronounced alterations in microglial transcriptomic profile, including upregulation of ApoE. Despite increased microglial recruitment to Aβ plaques upon SCFA supplementation, microglia contained less intracellular Aβ. Taken together, our results demonstrate that microbiota-derived SCFA are critical mediators along the gut-brain axis which promote Aβ deposition likely via modulation of the microglial phenotype.