The Alzheimer’s β-secretase BACE1 localizes to normal presynaptic terminals and to dystrophic presynaptic terminals surrounding amyloid plaques
Open accessAbstract
β-Site amyloid precursor protein (APP) cleaving enzyme-1 (BACE1) is the β-secretase that initiates Aβ production in Alzheimer's disease (AD). BACE1 levels are increased in AD, which could contribute to pathogenesis, yet the mechanism of BACE1 elevation is unclear. Furthermore, the normal function of BACE1 is poorly understood. We localized BACE1 in the brain at both the light and electron microscopic levels to gain insight into normal and pathophysiologic roles of BACE1 in health and AD, respectively. Our findings provide the first ultrastructural evidence that BACE1 localizes to vesicles (likely endosomes) in normal hippocampal mossy fiber terminals of both non-transgenic and APP transgenic (5XFAD) mouse brains. In some instances, BACE1-positive vesicles were located near active zones, implying a function for BACE1 at the synapse. In addition, BACE1 accumulated in swollen dystrophic autophagosome-poor presynaptic terminals surrounding amyloid plaques in 5XFAD cortex and hippocampus. Importantly, accumulations of BACE1 and APP co-localized in presynaptic dystrophies, implying increased BACE1 processing of APP in peri-plaque regions. In primary cortical neuron cultures, treatment with the lysosomal protease inhibitor leupeptin caused BACE1 levels to increase; however, exposure of neurons to the autophagy inducer trehalose did not reduce BACE1 levels. This suggests that BACE1 is degraded by lysosomes but not by autophagy. Our results imply that BACE1 elevation in AD could be linked to decreased lysosomal degradation of BACE1 within dystrophic presynaptic terminals. Elevated BACE1 and APP levels in plaque-associated presynaptic dystrophies could increase local peri-plaque Aβ generation and accelerate amyloid plaque growth 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 [5]
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- Authors
- Kandalepas, P. C., Sadleir, K. R., Eimer, W. A., Zhao, J., Nicholson, D. A., & Vassar, R.
- Affiliations
- Northwestern University (US)
- GlaxoSmithKline (China) (CN)
- Rush University Medical Center (US)
- Corresponding author
- Vassar, Robert
- Venue
- Acta Neuropathologica
- Published
- 2013-07-03
- Volume
- 126
- Issue
- 3
- Pages
- 329-352
- ISSN
- 0001-6322 (ISSN-L)
- 1432-0533
- PMC
- PMC3753469
- OpenAlex
- W2069248995
- Cited by
- 240
- References
- 126
- Citations by year
- 2026: 9 · 2025: 20 · 2024: 20 · 2023: 14 · 2022: 15 · 2021: 14 · 2020: 20 · 2019: 25 · 2018: 21 · 2017: 20 · 2016: 20 · 2015: 21 · 2014: 16 · 2013: 4
- FWCI
- 14.12
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Acta Neuropathologica (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- Northwestern University (CA060553, NCI CCSG P30 CA060553, P30CA060553, CCSG P30 CA060553)
- Rush University
- National Institutes of Health (CCSG P30, CA-060553, AG022560, NCI CCSG P30 CA060553, CCSG P30 CA060553, AG017139)
- Robert H. Lurie Comprehensive Cancer Center (P30CA060553, CCSG P30 CA060553, CA060553, NCI CCSG P30 CA060553)
- National Institute on Aging (RF1AG022560, R00AG031574, R01AG030142, R01AG017139, R01AG022560, R01AG047073)
- National Cancer Institute (NCI CCSG P30 CA060553, CA 060553, CCSGP30CA060553, P30CA060553)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- BACE1, beta-secretase, Alzheimer's disease, amyloid plaques, presynaptic terminals, amyloid precursor protein, amyloid-beta production, mossy fiber terminals, active zone, autophagy, lysosomal degradation, leupeptin, trehalose, 5xFAD mice, hippocampus, ultrastructure
- MeSH terms
- Alzheimer Disease, Animals, Autophagy, Humans, Mice, Transgenic, Synapses, Aspartic Acid Endopeptidases, Presynaptic Terminals, Mice, Amyloid Precursor Protein Secretases, Plaque, Amyloid
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