BACE1 elevation engendered by GGA3 deletion increases β-amyloid pathology in association with APP elevation and decreased CHL1 processing in 5XFAD mice
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BACKGROUND: β-site amyloid precursor protein cleaving enzyme 1 (BACE1) is the rate-limiting enzyme in the production of amyloid beta (Aβ), the toxic peptide that accumulates in the brains of Alzheimer's disease (AD) patients. Our previous studies have shown that the clathrin adaptor Golgi-localized γ-ear-containing ARF binding protein 3 (GGA3) plays a key role in the trafficking of BACE1 to lysosomes, where it is normally degraded. GGA3 depletion results in BACE1 stabilization both in vitro and in vivo. Moreover, levels of GGA3 are reduced and inversely related to BACE1 levels in post-mortem brains of AD patients. METHOD: In order to assess the effect of GGA3 deletion on AD-like phenotypes, we crossed GGA3 -/- mice with 5XFAD mice. BACE1-mediated processing of APP and the cell adhesion molecule L1 like protein (CHL1) was measured as well as levels of Aβ42 and amyloid burden. RESULTS: In 5XFAD mice, we found that hippocampal and cortical levels of GGA3 decreased while BACE1 levels increased with age, similar to what is observed in human AD brains. GGA3 deletion prevented age-dependent elevation of BACE1 in GGA3KO;5XFAD mice. We also found that GGA3 deletion resulted in increased hippocampal levels of Aβ42 and amyloid burden in 5XFAD mice at 12 months of age. While levels of BACE1 did not change with age and gender in GGAKO;5XFAD mice, amyloid precursor protein (APP) levels increased with age and were higher in female mice. Moreover, elevation of APP was associated with a decreased BACE1-mediated processing of CHL1 not only in 12 months old 5XFAD mice but also in human brains from subjects affected by Down syndrome, most likely due to substrate competition. CONCLUSION: This study demonstrates that GGA3 depletion is a leading candidate mechanism underlying elevation of BACE1 in AD. Furthermore, our findings suggest that BACE1 inhibition could exacerbate mechanism-based side effects in conditions associated with APP elevation (e.g. Down syndrome) owing to impairment of BACE1-mediated processing of CHL1. Therefore, therapeutic approaches aimed to restore GGA3 function and to prevent the down stream effects of its depletion (e.g. BACE1 elevation) represent an attractive alternative to BACE inhibition for the prevention/treatment of AD.
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GGA3 regulates BACE1 trafficking to lysosomes and modulates BACE1 levels; depletion and overexpression of GGA3 inversely regulate BACE1 levels.
“The Golgi-localized, γ-ear-containing clathrin adaptor ARF binding protein 3 (GGA3) regulates the trafficking of BACE1 to lysosomes, and modulates BACE1 levels through interactions with ubiquitin sorting machinery, where depletion and overexpression of GGA3 inversely regulates BACE1 levels [49, 50].”
From Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020) · cites this paper as [49]
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- Authors
- Kim, W., Ma, L., Lomoio, S., Willen, R., Lombardo, S., Dong, J., Haydon, P. G., & Tesco, G.
- Affiliations
- Tufts University (US)
- Corresponding author
- Tesco, Giuseppina
- ORCID
- Venue
- Molecular Neurodegeneration
- Published
- 2018-02-02
- Volume
- 13
- Issue
- 1
- Pages
- 6-6
- ISSN
- 1750-1326 (ISSN-L)
- PMC
- PMC5796504
- OpenAlex
- W2786152420
- Cited by
- 32
- References
- 87
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 6 · 2023: 1 · 2022: 5 · 2021: 3 · 2020: 5 · 2019: 6 · 2018: 2
- FWCI
- 2.74
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Molecular Neurodegeneration (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Institute on Aging (R01AG025952)
- National Institute of Neurological Disorders and Stroke (R01NS092497)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- ACE1, GGA3, Alzheimer's disease, amyloid-beta, APP processing, 5xFAD mice, lysosomal degradation, substrate competition, Down syndrome, amyloid burden, hippocampus, clathrin adaptor proteins
- MeSH terms
- Adult, Aged, Alzheimer Disease, Animals, Brain, Down Syndrome, Female, Humans, Male, Middle Aged, Cell Adhesion Molecules, Amyloid beta-Peptides, Aspartic Acid Endopeptidases, Amyloid beta-Protein Precursor, Mice, Knockout, Adaptor Proteins, Vesicular Transport, Mice, Amyloid Precursor Protein Secretases
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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.
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