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.
Highlights
Human genetic evidence and studies in App-knock-out (KO) mice indicate that the amyloid precursor protein (APP) plays an important physiological role in the central nervous system
As an initial step toward the generation of biological tools to test the hypothesis, we mapped the APP intracellular domain that interacts with the exocytosis machinery, and used a proteomic approach to identify the brain proteins that interact with the N-terminus (JCasp) and C-terminus (Ccas) sub-domains of the APP intracellular region
The brain interactome of ALID2 comprises most of the key proteins of the presynaptic release machinery that bind to JCasp and activation-induced cytidine deaminase (AID) (Table 2, Source Data were uploaded to the PRIDE repository – European Bioinformatics Institute (EBI), Cambridge, UK – with Proteome Xchange identifier #58725)
Summary
Human genetic evidence and studies in App-knock-out (KO) mice indicate that the amyloid precursor protein (APP) plays an important physiological role in the central nervous system. A polymorphism in APP that reduces APP processing protects from sporadic Alzheimer’s disease (AD) and normal aging-dependent cognitive decline (De Strooper and Voet, 2012, Jonsson et al, 2012). Analysis of App-KO mice has suggested a synaptic role for APP (Korte et al, 2012, Marcello et al, 2012, Octave et al, 2013, Randall et al, 2010, Turner et al, 2003, Venkitaramani et al, 2007). Long-term potentiation (LTP), a form of synaptic plasticity that underlies memory formation, is impaired in App-KO mice; and these LTP deficits are clearly noticeable in Fanutza et al eLife 2015;4:e09743.
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