title: APP and APLP2 interact with the synaptic release machinery and facilitate transmitter release at hippocampal synapses.
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.
authors.affiliation: Department of Microbiology and Immunology, Albert Einstein College of Medicine, New York, United States.
authors.forename: Tomas
authors.initials: T
authors.lastname: Fanutza
authors.affiliation: Department of Microbiology and Immunology, Albert Einstein College of Medicine, New York, United States.
authors.forename: Dolores
authors.initials: D
authors.lastname: Del Prete
authors.affiliation: MS Bioworks, LLC, Ann Arbor, United States.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Ford
authors.affiliation: Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, New York, United States.
authors.forename: Pablo E
authors.initials: PE
authors.lastname: Castillo
authors.affiliation: Department of Microbiology and Immunology, Albert Einstein College of Medicine, New York, United States.
authors.forename: Luciano
authors.initials: L
authors.lastname: D'Adamio
mesh_terms: D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D017353:Gene Deletion; D006624:Hippocampus / Q000502:physiology*; D008810:Mice, Inbred C57BL; D018377:Neurotransmitter Agents / Q000378:metabolism*; D011485:Protein Binding; D025941:Protein Interaction Mapping; D013569:Synapses / Q000502:physiology*; D009435:Synaptic Transmission
chemical_list: D016564:Amyloid beta-Protein Precursor; C492952:Aplp2 protein, mouse; D018377:Neurotransmitter Agents
keywords: Amyloid precursor protein; Dementia; mouse; neurodegeneration; neuroscience; synaptic transmission; synaptic vesicles