Depletion of GGA1 and GGA3 Mediates Postinjury Elevation of BACE1
Open accessAbstract
Traumatic brain injury (TBI) is one of the most robust environmental risk factors for Alzheimer's disease (AD). Compelling evidence is accumulating that a single event of TBI is associated with increased levels of Aβ. However, the underlying molecular mechanisms remain unknown. We report here that the BACE1 interacting protein, GGA3, is depleted while BACE1 levels increase in the acute phase after injury (48 h) in a mouse model of TBI. We further demonstrated the role of GGA3 in the regulation of BACE1 in vivo by showing that BACE1 levels are increased in the brain of GGA3-null mice. We next found that head trauma potentiates BACE1 elevation in GGA3-null mice in the acute phase after TBI, and discovered that GGA1, a GGA3 homolog, is a novel caspase-3 substrate depleted at 48 h after TBI. Moreover, GGA1 silencing potentiates BACE1 elevation induced by GGA3 deletion in neurons in vitro , indicating that GGA1 and GGA3 synergistically regulate BACE1. Accordingly, we found that levels of both GGA1 and GGA3 are depleted while BACE1 levels are increased in a series of postmortem AD brains. Finally, we show that GGA3 haploinsufficiency results in sustained elevation of BACE1 and Aβ levels while GGA1 levels are restored in the subacute phase (7 d) after injury. In conclusion, our data indicate that depletion of GGA1 and GGA3 engender a rapid and robust elevation of BACE1 in the acute phase after injury. However, the efficient disposal of the acutely accumulated BACE1 solely depends on GGA3 levels in the subacute phase of injury.
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Depletion of GGA3 resulted in reduced degradation of BACE1 in lysosomes and increased Ab production, similar to Bin1-depleted cells.
“The depletion of GGA3, which recognizes ubiquitinated BACE1, resulted in the reduced degradation of BACE1 in the lysosomes and increased Ab production in a similar manner to that observed in Bin1-depleted cells (30,41).”
From BIN1 regulates BACE1 intracellular trafficking and amyloid-β production (2016) · cites this paper as [41]
The Introduction states that GGA3 depletion impairs BACE1 sorting to lysosomes, where BACE1 is normally degraded. The Results report increased Aβ in Gga3-null primary neuronal cultures, but no increase in young adult Gga3-null mouse brains. Our copy does not establish that GGA3 recognizes ubiquitinated BACE1 or assess the comparison with Bin1-depleted cells. (LLM, conf=0.85)
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“Our aim was to assess -secretase activity, and since increases in BACE1 activity have previously been shown to increase both A 40 and A 42 (Vassar et al., 1999), we did not measure A 42 in these experiments.”
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- Authors
- Walker, K. R., Kang, E. L., Whalen, M. J., Shen, Y., & Tesco, G.
- Affiliations
- Tufts University (US)
- Harvard University (US)
- Roskamp Institute (US)
- Corresponding author
- Tesco, Giuseppina
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2012-07-25
- Volume
- 32
- Issue
- 30
- Pages
- 10423-10437
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC3490187
- OpenAlex
- W2008757745
- Cited by
- 66
- References
- 78
- Citations by year
- 2026: 3 · 2025: 3 · 2024: 2 · 2023: 1 · 2022: 2 · 2021: 2 · 2020: 3 · 2019: 5 · 2018: 3 · 2017: 4 · 2016: 14 · 2015: 7 · 2014: 8 · 2013: 7 · 2012: 1
- FWCI
- 4.93
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Cure Alzheimer's Fund
- National Institute on Aging (R01AG025888, R01AG033016, R01AG025952, R01AG034155)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Neurology › Traumatic Brain Injury and Neurovascular Disturbances
- Health Sciences › Medicine › Epidemiology › Traumatic Brain Injury Research
- Keywords
- GGA1, GGA3, BACE1, traumatic brain injury, Alzheimer's disease, amyloid-beta, head trauma
- MeSH terms
- Animals, Brain, Brain Injuries, Neurons, Aspartic Acid Endopeptidases, Mice, Knockout, Adaptor Proteins, Vesicular Transport, Mice, Caspase 3, Amyloid Precursor Protein Secretases
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