The DOI matches its Crossref record; 200 of the 201 references it cites were found in a registry or an index.
Amyloid-Beta Protein Clearance and Degradation (ABCD) Pathways and their Role in Alzheimer’s Disease
Open accessAbstract
Amyloid-β proteins (Aβ) of 42 (Aβ42) and 40 aa (Aβ40) accumulate as senile plaques (SP) and cerebrovascular amyloid protein deposits that are defining diagnostic features of Alzheimer's disease (AD). A number of rare mutations linked to familial AD (FAD) on the Aβ precursor protein (APP), Presenilin-1 (PS1), Presenilin- 2 (PS2), Adamalysin10, and other genetic risk factors for sporadic AD such as the ε4 allele of Apolipoprotein E (ApoE-ε4) foster the accumulation of Aβ and also induce the entire spectrum of pathology associated with the disease. Aβ accumulation is therefore a key pathological event and a prime target for the prevention and treatment of AD. APP is sequentially processed by β-site APP cleaving enzyme (BACE1) and γ-secretase, a multisubunit PS1/PS2-containing integral membrane protease, to generate Aβ. Although Aβ accumulates in all forms of AD, the only pathways known to be affected in FAD increase Aβ production by APP gene duplication or via base substitutions on APP and γ-secretase subunits PS1 and PS2 that either specifically increase the yield of the longer Aβ42 or both Aβ40 and Aβ42. However, the vast majority of AD patients accumulate Aβ without these known mutations. This led to proposals that impairment of Aβ degradation or clearance may play a key role in AD pathogenesis. Several candidate enzymes, including Insulin-degrading enzyme (IDE), Neprilysin (NEP), Endothelin-converting enzyme (ECE), Angiotensin converting enzyme (ACE), Plasmin, and Matrix metalloproteinases (MMPs) have been identified and some have even been successfully evaluated in animal models. Several studies also have demonstrated the capacity of γ-secretase inhibitors to paradoxically increase the yield of Aβ and we have recently established that the mechanism is by skirting Aβ degradation. This review outlines major cellular pathways of Aβ degradation to provide a basis for future efforts to fully characterize the panel of pathways responsible for Aβ turnover.
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
“cerebrospinal fluid (CSF) levels of the angiotensin-converting enzyme (ACE) are associated with Aβ levels81 and LOAD risk82, and studies show ACE can inhibit Aβ toxicity and aggregation83.”
From Genetic meta-analysis of diagnosed Alzheimer’s disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing (2019) · cites this paper as [83]
In the citing paper
“In the hippocampus of AD patients, the enzymes IDE, ACE and NEP had decreased activity.30”
From Amyloid β-based therapy for Alzheimer’s disease: Challenges, successes and future (2023) · cites this paper as [30]
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
Neuropathological stageing of Alzheimer-related changes.
Braak, H., & Braak, E. (1991) · Acta Neuropathologica · doi:10.1007/bf00308809 · Cited by 16,123
The Amyloid Hypothesis of Alzheimer’s Disease: Progress and Problems on the Road to Therapeutics
Hardy, J., & Selkoe, D. J. (2002) · Science · doi:10.1126/science.1072994 · Cited by 13,864
Amyloid oligomers exacerbate tau pathology in a mouse model of tauopathy
Selenica, M.-L. B., Brownlow, M., Jimenez, J. P., Lee, D. C., Pena, G., Dickey, C. A., Gordon, M. N., & Morgan, D. (2013) · Neurodegenerative Diseases · doi:10.1159/000337230 · Cited by 10,359
Goate, A., Chartier-Harlin, M.-C., Mullan, M., Brown, J., Crawford, F., Fidani, L., Giuffra, L., Haynes, A., Irving, N., James, L., et al. (1991) · Nature · doi:10.1038/349704a0 · Cited by 4,659
Visse, R., & Nagase, H. (2003) · Circulation Research · doi:10.1161/01.res.0000070112.80711.3d · Cited by 4,575
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 2×
“tyl protease with an acid pH optimum, in an endosome where -secretase is also present and converts CTF to A [25, 45].”
BackgroundClinical and biomarker changes in dominantly inherited Alzheimer's disease
Bateman, R. J., Xiong, C., Benzinger, T. L. S., Fagan, A. M., Goate, A., Fox, N. C., Marcus, D. S., Cairns, N. J., Xie, X., Blazey, T. M., et al. (2012) · New England Journal of Medicine · doi:10.1056/nejmoa1202753 · Cited by 3,814
Rigat, B., Hubert, C., Alhenc-Gelas, F., Cambien, F., Corvol, P., & Soubrier, F. (1990) · Journal of Clinical Investigation · doi:10.1172/jci114844 · Cited by 3,767
Structure and function of matrix metalloproteinases and TIMPs
Nagase, H., Visse, R., & MURPHY, G. (2006) · Cardiovascular Research · doi:10.1016/j.cardiores.2005.12.002 · Cited by 3,507
2013 Alzheimer's disease facts and figures
Thies, W. H., & Bleiler, L. (2013) · Alzheimer s & Dementia · doi:10.1016/j.jalz.2013.02.003 · Cited by 3,372
Research works printed but not linked: 1
- [23]Sambamurti K Greig NH Utsuki T Barnwell EL Sharma E Mazell C Targets for AD treatment: conflicting messages from gamma-secretase inhibitors J Neurochem 117 3 359 74 2011 21320126 PMC3076515
Cited by
Sorted by citations
Alzheimer Disease Genetics Consortium (ADGC), Kunkle, B. W., The European Alzheimer’s Disease Initiative (EADI), Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium (CHARGE), Genetic and Environmental Risk in AD/Defining Genetic, P. A. E. R. F. A. D. C. (., Grenier-Boley, B., Sims, R., Bis, J. C., Damotte, V., Naj, A. C., et al. (2019) · Nature Genetics · doi:10.1038/s41588-019-0358-2 · Cited by 2,946
Amyloid β-based therapy for Alzheimer’s disease: Challenges, successes and future
Zhang, Y., Chen, H., Li, R., Sterling, K., & Song, W. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01484-7 · Cited by 988
“In the hippocampus of AD patients, the enzymes IDE, ACE and NEP had decreased activity.(30) AD model mice also showed the impaired Aβ degradation system.”
BackgroundPromoting the clearance of neurotoxic proteins in neurodegenerative disorders of ageing
Boland, B., Yu, W. H., Corti, O., Mollereau, B., Henriques, A., Bézard, E., Pastores, G., Rubinsztein, D. C., Nixon, R. A., Duchen, M. R., et al. (2018) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2018.109 · Cited by 566
Genetic diversity fuels gene discovery for tobacco and alcohol use
Saunders, G., Wang, X., Chen, F., Jang, S.-K., Liu, M., Wang, C., Gao, S., Jiang, Y., Khunsriraksakul, C., Otto, J. M., et al. (2022) · Nature · doi:10.1038/s41586-022-05477-4 · Cited by 481
Role of Plant Derived Alkaloids and Their Mechanism in Neurodegenerative Disorders
Hussain, G., Rasul, A., Anwar, H., Aziz, N., Razzaq, A., Wei, W., Ali, M., Li, J., & Li, X. (2018) · International Journal of Biological Sciences · doi:10.7150/ijbs.23247 · Cited by 352
Metadata
- Authors
- Baranello, R., Bharani, K., Padmaraju, V., Chopra, N., Lahiri, D., Greig, N., Pappolla, M., & Sambamurti, K.
- Affiliations
- Medical University of South Carolina (US)
- Indiana University – Purdue University Indianapolis (US)
- Indiana University Bloomington (US)
- National Institutes of Health (US)
- The University of Texas Medical Branch at Galveston (US)
- ORCID
- Venue
- Current Alzheimer Research
- Publisher
- Bentham Science Publishers Ltd.
- Published
- 2015-01-03
- Volume
- 12
- Issue
- 1
- Pages
- 32-46
- ISSN
- 1567-2050 (ISSN-L)
- PMC
- PMC4820400
- OpenAlex
- W2136334732
- Cited by
- 331
- References
- 201
- Citations by year
- 2026: 9 · 2025: 26 · 2024: 14 · 2023: 30 · 2022: 34 · 2021: 44 · 2020: 45 · 2019: 45 · 2018: 31 · 2017: 22 · 2016: 20 · 2015: 10
- FWCI
- 20.39
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Current Alzheimer Research (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- IUScholarWorks (Indiana University) (submittedVersion)
- Purdue University Indianapolis (Indiana University) (submittedVersion)
- Funders
- National Institutes of Health (5r21ag042804-02)
- National Institute on Aging (R21-AG042804, AG046200, R01AG022103, R21AG046200, AG042804)
- National Institute of General Medical Sciences (T32 GM08716-13, T32GM008716)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › 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
- amyloid-beta, Alzheimer's disease, amyloid-beta clearance, amyloid beta degradation, amyloid plaques, familial Alzheimer's disease, APP mutations, presenilin, gamma-secretase, BACE1, insulin-degrading enzyme, neprilysin, matrix metalloproteinases, APOE ε4, gamma-secretase inhibitors
- MeSH terms
- Alzheimer Disease, Animals, Apolipoproteins E, Humans, Models, Biological, Mutation, Signal Transduction, Amyloid beta-Peptides, Presenilin-1, Presenilin-2, 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
