Cited by 40Alzheimer's disease research and treatmentsNeuroscience and Neuropharmacology ResearchNeuroinflammation and Neurodegeneration Mechanisms

Facilitation of glutamate, but not GABA, release in Familial Alzheimer's APP mutant Knock‐in rats with increased β‐cleavage of APP

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Tambini, Marc D., Yao, Wen, D'Adamio, Luciano·2019·Aging Cell

Abstract

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 (Apps) knock‐in rats, which carry an App mutation that causes familial Alzheimer's disease (FAD) in humans. We show that in Apps rats, β‐cleavage of APP is favored over α‐cleavage. Apps 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, Apps 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.

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Authors
Tambini, M. D., Yao, W., & D'Adamio, L.
Affiliations
Rutgers, The State University of New Jersey (US)
Corresponding author
D'Adamio, Luciano
Venue
Aging Cell
Publisher
Wiley
Published
2019-09-09
Volume
18
Issue
6
Pages
e13033-e13033
ISSN
  • 1474-9718 (ISSN-L)
  • 1474-9726
OpenAlex
W2972955744
Cited by
40
References
48
Citations by year
2026: 4 · 2025: 2 · 2024: 6 · 2023: 7 · 2022: 4 · 2021: 6 · 2020: 11
FWCI
3.59
Type
journal article
Language
en
Open access
Locations
  • Aging Cell (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
National Institute on Aging (R01 AG033007, R01 AG052286, R01 AG063407)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
amyloid precursor protein, BACE1, glutamate release, GABA release, familial Alzheimer's disease, glutamatergic synapses, dementia
MeSH terms
Alzheimer Disease, Animals, Female, gamma-Aminobutyric Acid, Male, Mutation, Aspartic Acid Endopeptidases, Amyloid beta-Protein Precursor, Glutamic Acid, Rats, Amyloid Precursor Protein Secretases

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