Facilitation of glutamate, but not GABA, release in Familial Alzheimer's APP mutant Knock‐in rats with increased β‐cleavage of APP
Open accessAbstract
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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The Apph allele enables the physiological production of human Aβ instead of rodent Aβ from the endogenous rat App gene.
“The Apph allele enables the physiological production of human Aβ instead of rodent Aβ from the endogenous rat App gene [43–49].”
APOE isoforms may impact neurite growth differently and affect neuronal cell survival in an isoform-dependent manner.
“Additionally, APOE isoforms may impact neurite growth differently [13] and affect neuronal cell survival in an isoform-dependent manner [14].”
From Analysis of early effects of human APOE isoforms on Alzheimer’s disease and type III hyperlipoproteinemia pathways using knock-in rat models with humanized APP and APOE (2024) · cites this paper as [13]
The Introduction discusses APP processing and synaptic vesicle release, not APOE isoforms. Searches of our full-text copy for APOE, neurite growth, and isoform-dependent neuronal survival found no passage addressing either effect. No page numbers were available in the indexed passages. (LLM, conf=0.77)
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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
- PMC
- PMC6826143
- 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
- gold
- doi.org
- Licence
- 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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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