ArticleMolecular neurodegeneration2018
BACE1 elevation engendered by GGA3 deletion increases β-amyloid pathology in association with APP elevation and decreased CHL1 processing in 5XFAD mice.
Article in Molecular neurodegeneration, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed, 30 citations in OpenAlex.
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- Taming microglia: the promise of engineered microglia in treating neurological diseases.Journal of neuroinflammation · 2024Review
- Microcurrent therapy as the nonpharmacological new protocol against Alzheimer's disease.Frontiers in aging neuroscience · 2024Article
- Nanotechnology-based gene therapy as a credible tool in the treatment of Alzheimer's disease.Neural regeneration research · 2023Review
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- Deubiquitinases in Neurodegeneration.Cells · 2022Review
- Spermine protects aluminium chloride and iron-induced neurotoxicity in rat model of Alzheimer's disease via attenuation of tau phosphorylation, Amyloid-β (1-42) and NF-κB pathway.Inflammopharmacology · 2021Article
- Mitochondrially-Targeted Therapeutic Strategies for Alzheimer's Disease.Current Alzheimer research · 2021Review
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- Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer's disease.Molecular neurodegeneration · 2020Review
- Upregulation of Alzheimer's Disease Amyloid-β Protein Precursor in Astrocytes Both in vitro and in vivo.Journal of Alzheimer's disease : JAD · 2020Article
- Echinacoside Suppresses Amyloidogenesis and Modulates F-actin Remodeling by Targeting the ER Stress Sensor PERK in a Mouse Model of Alzheimer's Disease.Frontiers in cell and developmental biology · 2020Article
- 5,6,7,4'-Tetramethoxyflavanone protects against neuronal degeneration induced by dexamethasone by attenuating amyloidogenesis in mice.EXCLI journal · 2020Article
- BACE1 partial deletion induces synaptic plasticity deficit in adult mice.Scientific reports · 2019Article
- Subtyping of circulating exosome-bound amyloid β reflects brain plaque deposition.Nature communications · 2019Article
- Review
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8 authors at 1 institution in 1 country.
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Abstract
backgroundβ-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.
methodIn 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.
resultsIn 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.
conclusionThis 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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