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Mechanisms of Amyloid-β Peptide Clearance: Potential Therapeutic Targets for Alzheimer's Disease
Open accessAbstract
Amyloid-β peptide (Aβ) is still best known as a molecule to cause Alzheimer's disease (AD) through accumulation and deposition within the frontal cortex and hippocampus in the brain. Thus, strategies on developing AD drugs have been focused on the reduc-tion of Aβ in the brain. Since accumulation of Aβ depends on the rate of its synthesis and clearance, the metabolic pathway of Aβ in the brain and the whole body should be carefully explored for AD research. Although the synthetic pathway of Aβ is equally important, we summarize primarily the clearance pathway in this paper because the former has been extensively reviewed in previous studies. The clearance of Aβ from the brain is accomplished by several mechanisms which include non-enzymatic and enzymatic pathways. Nonenzymatic pathway includes interstitial fluid drainage, uptake by microglial phagocytosis, and transport across the blood vessel walls into the circulation. Multiple Aβ-degrading enzymes (ADE) implicated in the clearance process have been identified, which include neprilysin, insulin-degrading enzyme, matrix metalloproteinase-9, glutamate carboxypeptidase II and others. A series of studies on Aβ clearance mechanism provide new insight into the pathogenesis of AD at the molecular level and suggest a new target for the development of novel therapeutics.
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“forming a protective barrier to protect brain tissue from the neurotoxicity of Aβ plaques”
From Acoustofluidic assembly of 3D neurospheroids to model Alzheimer's disease (2020) · cites this paper as [47]
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“promotes the clearance of Aβ aggregates.47, 48”
From Acoustofluidic assembly of 3D neurospheroids to model Alzheimer's disease (2020) · cites this paper as [47]
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“The Aβ clearance may occur through the transport into the cerebrospinal fluid, the blood across the blood-brain barrier (BBB), and the removal by brain-resident macrophages (Yoon and Jo, 2012).”
From Exploring the Therapeutic Potential of Phytochemicals in Alzheimer’s Disease: Focus on Polyphenols and Monoterpenes (2022) · cites this paper as Yoon and Jo, 2012
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“Mononuclear phagocytes in the brain, known as microglia, have the ability to clear Aꞵ through degradation of soluble and fibrillar forms (Yoon and Jo 2012 ).”
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Targeted Protein Degrader from Ginkgo to Mitigate Amyloid β-Induced Neurotoxicity
Dutta, B., Loo, S., Kam, A., Liu, C., & Tam, J. P. (2026) · Biochemistry · doi:10.1021/acs.biochem.5c00763 · Cited by 1
Tripathi, P., & Shah, J. (2026) · Neurochemical Research · doi:10.1007/s11064-026-04721-x · Cited by 1
Association between Cerebral Small Vessel and Alzheimer’s Disease
Lee, K. H., & Kang, K. M. (2022) · Journal of the Korean Society of Radiology · doi:10.3348/jksr.2022.0041 · Cited by 1
“는 것으로 알려져 있는데(25), 이를 통한 과정이 원활하지 않을 때 알츠하이머병 진행이 촉진된다 고 알려져 있다(26).”
Aging and brain free cholesterol concentration on amyloid‐β peptide accumulation in guinea pigs
Pang, K. S., Peng, H., Li, B. P., Wen, B., Noh, K., Xia, R., Toscan, A., Serson, S., Fraser, P. E., Tirona, R. G., et al. (2024) · Biopharmaceutics & Drug Disposition · doi:10.1002/bdd.2386 · Cited by 1
“…‐ onset) form of Alzheimer’s disease due to reduced A β peptide catabolism by neprilysin (Briones & Darw-ish, 2013; Hardy & Selkoe, 2002; Iwata et al., 2005; Yoon & Jo, 2012), and efflux by P ‐ gp and LRP1 (Briones & Darwish, 2013; Iwata et al., 2005; Shibata et al., 2000; Toornvliet et al., 2006).”
BackgroundMavroudis, I. A., Petridis, F., Kazis, D. A., Ionescu, C., Novac, B., Petroaie, A. D., Novac, O., Gurzu, I. L., & Gurzu, B. (2025) · BRAIN BROAD RESEARCH IN ARTIFICIAL INTELLIGENCE AND NEUROSCIENCE · doi:10.70594/brain/16.2/1 · Cited by 1
Contribution of Neuroinflammation in the Pathogenesis of Alzheimer’s Disease
Farooqui, A. A. (2017) · Elsevier eBooks · doi:10.1016/b978-0-12-809937-7.00006-9 · Cited by 1
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“Beta-amyloid clearance is a well-studied process in relation to Alzheimer’s in the human brain, where several are proteases and peptidase are secreted, in response to extracellular beta-amyloid accumulation (Panza et al., 2019; Yoon and Jo, 2012).”
BackgroundAlzheimer’s disease as a syndrome of overloaded amyloidic synaptic tagging in memory networksPreprint
Murphy, N. (2021) · OSF Preprints (OSF Preprints) · doi:10.31219/osf.io/7gsaz
Research Progress of Stem Cell Exosomes in Alzheimer’s Disease
古, 良. (2023) · Bioprocess · doi:10.12677/bp.2023.132013
Linking the Meso and Macroscale Determinants of Cerebral AgeingPreprint
Paolo, R. D., Deery, H. A., & Jamadar, S. D. (2023) · PsyArXiv (OSF Preprints) · doi:10.31234/osf.io/8n4ud
Singh, S., Sharma, N., Singh, V. P., & Sharma, A. (2025) · Current Nanomedicine · doi:10.2174/0124681873330947241230054603
Therapeutic Strategies Targeting Amyloid-β in Alzheimer’s Disease
Tyagi, N., Pal, S., & Bisht, D. (2025) · Springer eBooks · doi:10.1007/978-981-96-6202-9_13 · Cited by 1
Infusion of blood from young and old mice modulates amyloid pathology
Pizarro, M., Gomez‐Gutierrez, R., Caviedes, A., Valdes, C., Woehlbier, U., Vargas, C., Hernández, M., Duran-Aniotz, C. A., & Morales, R. (2025) · Aging · doi:10.18632/aging.206319
“These findings underscore the diverse approaches that leverage blood-based mechanisms for Aβ clearance, providing valuable insights for the development of effective therapeutic interventions [25, 26].”
Kim, J., Wi, D., Han, S. N., & Park, C. Y. (2025) · Nutrients · doi:10.3390/nu17213339 · Cited by 1
Cortical Bone Loss and Fragility in a 2-Month Triple Transgenic Mouse Model of Alzheimer’s Disease
Storlino, G., Posa, F., Dell'Endice, T. S., Piccolo, F., Colaianni, G., Cassano, T., Grano, M., & Mori, G. (2025) · Cells · doi:10.3390/cells14221816
“Furthermore, it has been proven that the presence of A β plaques can increase bone resorption through the activation of osteoclastogenesis marker genes (Cathepsin K and TRAP) led by RANKL [25,26].”
Li, J., Liu, J., Zhou, M., Xu, J., Xiao, Y., Fan, X., & Xu, W. (2025) · Drug and Chemical Toxicology · doi:10.1080/01480545.2025.2592931
“Furthermore, PlaU dysfunction contributes to impaired amyloid-β (aβ) clearance mechanisms (Gaweda-Walerych et al., 2021; Yoon & Jo, 2012), with elevated PlaU expression correlating directly with compromised aβ clearance efficiency and enhanced aβ plaque deposition.”
Lin, G.-B., Liu, H.-H., Kuo, Y.-Y., Chen, Y.-M., Hsu, F.-T., Wang, Y.-W., Kung, Y., Ching, C., & Chao, C. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2025.12.10.693347
Phochantachinda, S., Chantong, B., Reamtong, O., & Chatchaisak, D. (2021) · Figshare · doi:10.6084/m9.figshare.13668053
Phochantachinda, S., Chantong, B., Reamtong, O., & Chatchaisak, D. (2021) · Figshare · doi:10.6084/m9.figshare.13668050
Phochantachinda, S., Chantong, B., Reamtong, O., & Chatchaisak, D. (2021) · Figshare · doi:10.6084/m9.figshare.13668059
Investigating gender differences in Alzheimer's disease
Fouad, G. I., Ando, H., & Ichihara, G. (2026) · Journal of Alzheimer s Disease · doi:10.1177/13872877251410204 · Cited by 2
“In the brain, A β is hydrolyzed through the proteolytic machinery, 131 and more than 20 different A β -degrading enzymes (ADEs) have been identi fi ed 132 ; metalloproteases are ADEs, with matrix metalloprotease 2 (MMP-2), MMP-7, and MMP-9 showing A β -degrading activity and association with AD.”
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Metadata
- Authors
- Yoon, S.-S., & AhnJo, S.-M.
- Affiliations
- Dankook University (KR)
- ORCID
- Yoon, Sang-Sun
- Venue
- Biomolecules and Therapeutics
- Published
- 2012-05-31
- Volume
- 20
- Issue
- 3
- Pages
- 245-255
- ISSN
- 1976-9148 (ISSN-L)
- PMC
- PMC3794520
- OpenAlex
- W2008487250
- Cited by
- 205
- References
- 122
- Citations by year
- 2026: 15 · 2025: 27 · 2024: 27 · 2023: 23 · 2022: 14 · 2021: 26 · 2020: 18 · 2019: 15 · 2018: 11 · 2017: 9 · 2016: 6 · 2015: 9 · 2014: 1 · 2013: 3 · 2012: 1
- FWCI
- 0.49
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Biomolecules & Therapeutics (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- Funders
- National Research Foundation
- National Research Foundation of Korea (2011-0016127)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- amyloid-beta, Alzheimer's disease, amyloid-beta clearance, neprilysin, insulin-degrading enzyme, MMP-9, prostate-specific membrane antigen, microglial phagocytosis, interstitial fluid drainage, blood-brain barrier, therapeutic target
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