Open AccessFacilitation of glutamate, but not GABA , release in Familial Alzheimer's APP mutant Knock‐in rats with increased β‐cleavage of APP
Author(s) -
Tambini Marc D.,
Yao Wen,
D'Adamio Luciano
Publication year - 2019
Publication title -
aging cell
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.103
H-Index - 140
eISSN - 1474-9726
pISSN - 1474-9718
DOI - 10.1111/acel.13033
Subject(s) - glutamate receptor , amyloid precursor protein , glutamatergic , mutant , biology , synaptic vesicle , cleavage (geology) , amyloid precursor protein secretase , microbiology and biotechnology , biochemistry , neuroscience , alzheimer's disease , vesicle , medicine , gene , disease , receptor , paleontology , membrane , fracture (geology)
Amyloid precursor protein ( APP ) modulates glutamate release via cytoplasmic and intravesicular interactions with the synaptic vesicle release machinery. The intravesicular domain, called ISVAID , contains the BACE 1 cleavage site of APP . We have tested the functional significance of BACE 1 processing of APP using App ‐Swedish ( App s ) knock‐in rats, which carry an App mutation that causes familial Alzheimer's disease ( FAD ) in humans. We show that in App s rats, β‐cleavage of APP is favored over α‐cleavage. App s rats show facilitated glutamate, but not GABA , release. Our data support the notion that APP tunes glutamate release, and that BACE 1 cleavage of the ISVAID segment of APP facilitates this function. We define this phenomenon as BACE 1 on APP ‐dependent glutamate release ( BAD ‐Glu). Unsurprisingly, App s rats show no evidence of AD ‐related pathology at 15 days and 3 months of age, indicating that alterations in BAD ‐Glu are not caused by pathological lesions. The evidence that a pathogenic APP mutation causes an early enhancement of BAD ‐Glu suggests that alterations of BACE 1 processing of APP in glutamatergic synaptic vesicles could contribute to dementia.