The DOI matches its Crossref record; 124 of the 126 references it cites were found in a registry or an index.
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.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“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]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
LC3, a mammalian homologue of yeast Apg8p, is localized in autophagosome membranes after processing.
Kabeya, Y., Mizushima, N., Ueno, T., Yamamoto, A., Kirisako, T., Noda, T., Kominami, E., Ohsumi, Y., & Yoshimori, T. (2000) · The EMBO Journal · doi:10.1093/emboj/19.21.5720 · Cited by 6,605
Vassar, R., Bennett, B. D., Babu-Khan, S., Kahn, S., Mendiaz, E. A., Denis, P., Teplow, D. B., Ross, S., Amarante, P., Loeloff, R., et al. (1999) · Science · doi:10.1126/science.286.5440.735 · Cited by 3,876 · cited 4×
“4g), suggesting vesicular localization, as expected [106].”
BackgroundInfluentialSelf-citationOakley, H., Cole, S. L., Logan, S., Maus, E., Shao, P., Craft, J., Guillozet-Bongaarts, A., Ohno, M., Disterhoft, J., Van Eldik, L., et al. (2006) · The Journal of Neuroscience · doi:10.1523/jneurosci.1202-06.2006 · Cited by 3,530 · cited 2×
“5XFAD mice have been described previously [75] and were maintained on a B6/SJL F1 hybrid background.”
MethodSelf-citationTwenty years of the Alzheimer's disease amyloid hypothesis: a genetic perspective
Tanzi, R. E., & Bertram, L. (2005) · Cell · doi:10.1016/j.cell.2005.02.008 · Cited by 1,849
APP Processing and Synaptic Function
Kamenetz, F., Tomita, T., Hsieh, H., Seabrook, G., Borchelt, D., Iwatsubo, T., Sisodia, S., & Malinow, R. (2003) · Neuron · doi:10.1016/s0896-6273(03)00124-7 · Cited by 1,644
Purification and cloning of amyloid precursor protein β-secretase from human brain
Sinha, S., Anderson, J. P., Barbour, R., Basi, G. S., Caccavello, R., Davis, D., Doan, M., Dovey, H. F., Frigon, N., Hong, J., et al. (1999) · Nature · doi:10.1038/990114 · Cited by 1,612
Self-citationExtensive Involvement of Autophagy in Alzheimer Disease: An Immuno-Electron Microscopy Study
Nixon, R. A., Wegiel, J., Kumar, A., Yu, W. H., Peterhoff, C., Cataldo, A., & Cuervo, A. M. (2005) · Journal of Neuropathology & Experimental Neurology · doi:10.1093/jnen/64.2.113 · Cited by 1,588
Membrane-anchored aspartyl protease with Alzheimer's disease β-secretase activity
Yan, R., Bienkowski, M. J., Shuck, M. E., Miao, H., Tory, M. C., Pauley, A. M., Brashler, J. R., Stratman, N. C., Mathews, W. R., Buhl, A. E., et al. (1999) · Nature · doi:10.1038/990107 · Cited by 1,438
Tor, a Phosphatidylinositol Kinase Homologue, Controls Autophagy in Yeast
Noda, T., & Ohsumi, Y. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.7.3963 · Cited by 1,303
Synaptic Activity Regulates Interstitial Fluid Amyloid-β Levels In Vivo
Cirrito, J. R., Yamada, K. A., Finn, M. B., Sloviter, R. S., Bales, K. R., May, P. C., Schoepp, D. D., Paul, S. M., Mennerick, S., & Holtzman, D. M. (2005) · Neuron · doi:10.1016/j.neuron.2005.10.028 · Cited by 1,265
Flagged first, then by citations
2 of the 126 references couldn’t be matched to a known paper.
Cited by
Sorted by citations
Items 201–244 of 244
Xiao, X., Wang, X., Zhu, K., Li, L., He, Y., Zhang, J., Li, L., Hu, H., Cui, Y., Zhang, J., et al. (2023) · Molecular Psychiatry · doi:10.1038/s41380-023-02176-y · Cited by 3
Russo, M. L., Ayala, G. D., Neal, D., Rogalsky, A. E., Ahmad, S. J., Musial, T. F., Pearlman, M., Bean, L. A., Farooqi, A. K., Ahmed, A., et al. (2024) · Brain Research · doi:10.1016/j.brainres.2024.149083 · Cited by 3
Self-citationVassar, R. J. (2016) · Elsevier eBooks · doi:10.1016/b978-0-12-802173-6.00003-4 · Cited by 3
Self-citationNixon, R. A., Lee, J., Stavrides, P. H., Darji, S., Goulbourne, C. N., Berg, M. J., Mohan, P. S., Yang, D., Roussos, P., Bleiwas, C., et al. (2024) · Research Square · doi:10.21203/rs.3.rs-5306901/v1 · Cited by 3
BDNF alters β-cleavage of APP and subcellular distribution of BACE1
Hallam, R. D., Foran, G., Fletcher, N. K., MacPherson, R. E. K., & Necakov, A. (2026) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00642.2025 · Cited by 2
Lee, S., Ju, I. G., Eo, H., Kim, J. H., Choi, Y., & Oh, M. S. (2024) · Chinese Medicine · doi:10.1186/s13020-024-00966-2 · Cited by 3
Maekawa, K., Sobue, A., Komine, O., Saito, Y., Murayama, S., Saido, T. C., Saito, T., & Yamanaka, K. (2025) · Scientific Reports · doi:10.1038/s41598-025-98825-z · Cited by 4
Ramsden, C. E., Zamora, D., Horowitz, M. S., Jahanipour, J., Keyes, G. S., Li, X., Murray, H. C., Curtis, M. A., Faull, R. L. M., Sedlock, A. B., et al. (2023) · medRxiv · doi:10.21203/rs.3.rs-2968020/v1 · Cited by 2
Franke, B. U., Kummer, K. K., Rose‐John, S., Lichtenthaler, S. F., & Kress, M. (2025) · Cytokine · doi:10.1016/j.cyto.2025.156925 · Cited by 1
Salah, R. S., El‐Sayed, N. F., El‐Hussieny, M., Mansour, S. T., Othman, M., Fouad, M. A., Rashdan, H. R. M., Ewies, E. F., Gharib, H. S. A., & Elsayed, G. H. (2026) · RSC Advances · doi:10.1039/d5ra07584j · Cited by 1
Wang, Y., Sun, Z., Zhou, P., Tu, T., Zhang, X.-J., Tu, E., Chen, H., Cheng, H.-Y., Pan, A., Zhang, Q., et al. (2026) · Neuroscience · doi:10.1016/j.neuroscience.2026.03.032 · Cited by 1
Cholesterol Potentiates β-Amyloid Genesis in Cultured Human Umbilical Vein Endothelial Cells
Huang, G., Xue, Z., Hu, X., Wan, L., Li, J., Cai, Y., Patrylo, P. R., Luo, X.-G., Pan, A., & Yan, X. (2016) · Advances in Alzheimer s Disease · doi:10.4236/aad.2016.52002 · Cited by 1
Frontiers in Clinical Drug Research - Alzheimer Disorders
Atta-ur-rahman, Mavoungou, C., Zimmerman, K. S., Wright, J., Harding, J., Cavallaro, R., Fuso, A., Yoshiyama, Y., Asija, Z., Clifford, A., et al. (2015) · BENTHAM SCIENCE PUBLISHERS eBooks · doi:10.2174/97816810806801150301 · Cited by 1
Protein–Protein Interactions in Neurodegenerative Diseases
Poluri, K. M., Gulati, K., Tripathi, D. K., & Nagar, N. (2023) · Springer eBooks · doi:10.1007/978-981-99-2423-3_3 · Cited by 2
Gannon, P. J. (2014) · Scholarly Commons (University of Pennsylvania) · Cited by 1
Snead, A. M., Patel, S., Krout, M., Hippman, R. S., Smith, G., Dileep, D., Chagoor, N., Shi, R., Linares-Saldana, R., Dobria, A., et al. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.11.04.621986 · Cited by 2
Jordá-Siquier, T., Petrel, M., Kouskoff, V., Cordelières, F. P., Frykman, S., Müller, U. C., Mulle, C., & Barthet, G. (2020) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2020.10.16.342196 · Cited by 2
Jeppsson, F. (2016) · KTH Publication Database DiVA (KTH Royal Institute of Technology)
The role of novel genes in CNS axon regeneration
Almutiri, S. (2017) · University of Birmingham Institutional Research Archive (University of Birmingham)
Nakatomi, M., & Neu, H. C. (1986) · PubMed
Lundgren, J. L. (2018) · Figshare
Effects and Possible Mechanisms of Some Phytochemicals on Drosophila Models of Alzheimer’s Disease
왕설 (2016) · Seoul National University Open Repository (Seoul National University)
Yan, R. (2019) · Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature · doi:10.3410/f.736877185.793568031
Alzheimer’s disease beyond the amyloid accumulation
Urkon, M., & Nagy, E. E. (2022) · Orvostudományi Értesítö · doi:10.2478/orvtudert-2022-0002
Los trastornos neurocognitivos y retos de la epigenética
Salazar, J. D. M., Barrera, J. M. M., Martínez, J. A. P., Sánchez-Salcedo, S. S., & Jiménez, A. P. (2022) · Revista Biociencias · doi:10.18041/2390-0512/biociencias.2.10695
Simone, A. D., & Andrisano, V. (2024) · Neuromethods · doi:10.1007/978-1-0716-4232-0_2
Wang, Y., Zhang, Q.-L., Zhou, P., Tu, T., Sun, Z.-P., Zhang, X.-J., Tu, E., Chen, H., Cheng, H., Pan, A., et al. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.08.16.670658
BACE1 Expression Is Required for Proper Synaptic Vesicle Dynamics in the Hippocampus
Zhou, J., Antic, S. D., Das, B., He, W., Tran, D. M., Hu, X., Fernández‐Chacón, R., & Yan, R. (2025) · Journal of Neurochemistry · doi:10.1111/jnc.70299
Wang, T., Sobue, A., Watanabe, S., Komine, O., Saido, T. C., Saito, T., & Yamanaka, K. (2024) · Figshare · doi:10.6084/m9.figshare.25264361
Wang, T., Sobue, A., Watanabe, S., Komine, O., Saido, T. C., Saito, T., & Yamanaka, K. (2024) · Figshare · doi:10.6084/m9.figshare.25264480
Lee, S., Ju, I. G., Eo, H., Kim, J. H., Choi, Y., & Oh, M. S. (2024) · Figshare · doi:10.6084/m9.figshare.26182169
Wang, T., Sobue, A., Watanabe, S., Komine, O., Saido, T. C., Saito, T., & Yamanaka, K. (2024) · Figshare · doi:10.6084/m9.figshare.26684136
Fu, H., Li, J., Zhang, C., Gao, G., Ge, Q., & Daxiang, C. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2025.12.30.696965
Zhang, H.-X., & Li, H.-Y. (2026) · Medicine · doi:10.1097/md.0000000000048105
Rôle du peptide amyloïde dans les maladies neurodégénératives
Combes, M. (2018) · theses.fr (ABES) · doi:10.70675/a219ef4dzbca0z4272z8bf2z74080a1976e5 · Cited by 1
Physiological and pathological roles of the amyloid precursor protein at the presynapse
Jordá-Siquier, T. (2021) · theses.fr (ABES) · doi:10.70675/3bff9a77z3935z4d28zb02bz5b454bcbc77e
Moreira-de-Sá, A. (2024) · theses.fr (ABES) · doi:10.70675/3e418ab2ze9a3z43e4z9d87ze5870aefddac
Zakaria, J. A. D., & Vassar, R. J. (2026) · Topics in medicinal chemistry · doi:10.1007/7355_2026_188
Self-citationErişir, A., Maher, E. E., Anderson, Z., Chawla, S., Hanley, L., Zhao, A., Birisik, K., Toklucu, E. S., & Keskinöz, E. N. (2026) · Acta Neuropathologica Communications · doi:10.1186/s40478-026-02320-z
Neuronal overexpression of Nrf2 reduces dystrophic neurites in 5XFAD Alzheimer’s disease model mice
Sadleir, K. R., Gomez, K. P., Chandra, S., Ley, M. L., Khatri, A. W., Guo, J., Xue, Y., Cepko, C. L., & Vassar, R. J. (2026) · Alzheimer s Research & Therapy · doi:10.1186/s13195-026-02097-2
Self-citationYi, F., Ma, J., Zhao, R., Xie, Q., Lu, S., Zhang, K., Zhong, Z., Ouyang, H., Qin, Y., Xu, M., et al. (2026) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2026.179279
Sadleir, K. R. (2025) · Galter Health Sciences Library, Northwestern University · doi:10.18131/0m0ef-phj22
Self-citation
Metadata
- 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
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › 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
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.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
