β-Site Amyloid Precursor Protein Cleaving Enzyme 1 Levels Become Elevated in Neurons around Amyloid Plaques: Implications for Alzheimer's Disease Pathogenesis
Open accessAbstract
Beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) (beta-secretase) initiates generation of beta-amyloid (Abeta), which plays an early role in Alzheimer's disease (AD). BACE1 levels are increased in postmortem AD brain, suggesting BACE1 elevation promotes Abeta production and AD. Alternatively, the BACE1 increase may be an epiphenomenon of late-stage AD. To distinguish between these possibilities, we analyzed BACE1 elevation using a highly specific BACE1 antibody, BACE-Cat1, made in BACE1-/- mice, which mount a robust anti-BACE1 immune response. Previous BACE1 immunohistochemical studies lack consistent results because typical BACE1 antibodies produce nonspecific background, but BACE-Cat1 immunolabels BACE1 only. BACE1 elevation was recapitulated in two amyloid precursor protein (APP) transgenic mouse lines. 5XFAD mice form amyloid plaques at young ages and exhibit neuron loss. In contrast, Tg2576 form plaques at a more advanced age and do not show cell death. These two mouse lines allow differentiation between early Abeta-induced events and late phenomena related to neuron death. BACE1 levels became elevated in parallel with amyloid burden in each APP transgenic, starting early in 5XFAD and late in Tg2576. The increase in BACE1 protein occurred without any change in BACE1 mRNA level, indicating a posttranscriptional mechanism. In APP transgenic and AD brains, high BACE1 levels were observed in an annulus around Abeta42-positive plaque cores and colocalized with neuronal proteins. These results demonstrate that amyloid plaques induce BACE1 in surrounding neurons at early stages of pathology before neuron death occurs. We conclude that BACE1 elevation is most likely triggered by the amyloid pathway and may drive a positive-feedback loop in AD.
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BACE1 accumulates in neuritic dystrophies near Aβ plaques in AD mouse models and AD brains, most likely by a posttranslational mechanism.
“Notably, a relatively large accumulation of BACE1 was described in neuritic dystrophies in the vicinity of Aβ plaques both in AD amyloidogenic mouse models and in AD brains, most likely by a posttranslational mechanism (2,5,6).”
From The β-Secretase BACE1 in Alzheimer’s Disease (2021) · cites this paper as [2]
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- Authors
- Zhao, J., Fu, Y., Yasvoina, M., Shao, P., Hitt, B., O'Connor, T., Logan, S., Maus, E., Citron, M., Berry, R., Binder, L., & Vassar, R.
- Affiliations
- Northwestern University (US)
- Amgen (United States) (US)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2007-04-04
- Volume
- 27
- Issue
- 14
- Pages
- 3639-3649
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6672403
- OpenAlex
- W2080124845
- Cited by
- 365
- References
- 59
- Citations by year
- 2026: 7 · 2025: 16 · 2024: 13 · 2023: 17 · 2022: 13 · 2021: 22 · 2020: 10 · 2019: 15 · 2018: 20 · 2017: 12 · 2016: 19 · 2015: 20 · 2014: 29 · 2013: 28 · 2012: 26
- FWCI
- 15.36
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Funders
- National Institute on Aging (R01AG022560, P01AG021184)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- BACE1, beta-secretase, Alzheimer's disease, amyloid plaques, amyloid-beta, APP transgenic mice, 5xFAD mice, Tg2576 mice, post-transcriptional regulation, neuronal loss, positive feedback loop, amyloid pathology
- MeSH terms
- Aged, Aged, 80 and over, Alzheimer Disease, Animals, Female, Humans, Male, Mice, Inbred C57BL, Mice, Transgenic, Neurons, Aspartic Acid Endopeptidases, Mice, Knockout, Mice, Amyloid Precursor Protein Secretases, Plaque, Amyloid
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.
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