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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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“The amyloid-beta (A β ) peptide is a crucial element in the advancement of AD, and several studies have emphasized its association with lncRNAs in the pathogenesis of AD [43].”
BackgroundBeyond amyloid and tau: rethinking Alzheimer’s disease through less explored avenues
Gyimesi, M., Okolicsanyi, R. K., & Haupt, L. M. (2024) · Open Biology · doi:10.1098/rsob.240035 · Cited by 29
“…brains, the rates of Aβ synthesis and clearance are balanced, and Aβ fragments are cleared through various mechanisms, including via the actions of low-density lipoprotein receptor-related protein 1 (LRP1) and clusterin (CLU), or via enzymes such as neprylsin and matrix metalloproteinase-9 [39,40].”
BackgroundAmyloid Beta Hypothesis in Alzheimer's Disease: Major Culprits and Recent Therapeutic Strategies
Dileep, K. V., & Chandra, R. (2019) · Current Drug Targets · doi:10.2174/1389450120666190806153206 · Cited by 26
Tumour suppression through modulation of neprilysin signaling: A comprehensive review
Sankhe, R., Pai, K. S. R., & Kishore, A. (2020) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2020.173727 · Cited by 26
Blood-Brain Barrier Disruption Increases Amyloid-Related Pathology in TgSwDI Mice
Abdallah, I. M., Al-Shami, K. M., Yang, E., & Kaddoumi, A. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22031231 · Cited by 26
Ye, Y., Gao, M., Shi, W., Gao, Y., Li, Y., Yang, W., Zheng, X., & Lu, X. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1325530 · Cited by 27
Saxena, S. K., Ansari, S., Maurya, V. K., Kumar, S., Sharma, D. K., Malhotra, H., Tiwari, S., Srivastava, C., Paweska, J. T., Abdel-Moneim, A. S., et al. (2024) · ACS Pharmacology & Translational Science · doi:10.1021/acsptsci.4c00400 · Cited by 27
Shalaby, M. A., Nounou, H. A., & Deif, M. M. (2019) · The Egyptian Journal of Neurology Psychiatry and Neurosurgery · doi:10.1186/s41983-019-0094-7 · Cited by 24
Abdallah, I. M., Al-Shami, K. M., Alkhalifa, A. E., Al-Ghraiybah, N. F., Guillaume, C., & Kaddoumi, A. (2023) · Molecules · doi:10.3390/molecules28031249 · Cited by 27
“In the initial stages of AD, glial cells positively affect Aβ elimination by phagocytosis [15].”
BackgroundComparison of Synthetic Neuronal Model Membrane Mimics in Amyloid Aggregation at Atomic Resolution
Bera, S., Gayen, N., Mohid, S. A., Bhattacharyya, D., Krishnamoorthy, J., Sarkar, D., Choi, J., Sahoo, N., Mandal, A. K., Lee, D., et al. (2020) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.0c00166 · Cited by 23
Gu, M., Kim, J., & Yang, H. O. (2016) · Neurochemical Research · doi:10.1007/s11064-016-1857-5 · Cited by 22
Guan, Z., Chen, Z., Fu, S., Dai, L., & Shen, Y. (2020) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2020.00260 · Cited by 22
“Thus, enhancing microglial phagocytosis also be proposed as a potential therapeutic strategy for AD (Lee and Landreth, 2010; Yoon and Jo, 2012; Maleki and Rivest, 2019).”
BackgroundFaraji, P., Kühn, H., & Ahmadian, S. (2024) · Journal of Molecular Neuroscience · doi:10.1007/s12031-024-02224-4 · Cited by 25
Berman, S. E., Clark, L. R., Rivera‐Rivera, L. A., Norton, D., Racine, A. M., Rowley, H. A., Bendlin, B. B., Blennow, K., Zetterberg, H., Carlsson, C. M., et al. (2017) · Journal of Alzheimer s Disease · doi:10.3233/jad-170402 · Cited by 21
Amyloid beta-protein and lipid rafts focused on biogenesis and catabolism
Araki, W. (2015) · Frontiers in bioscience · doi:10.2741/4311 · Cited by 21
“Aβ clearance is additionally mediated by microglial phagocytosis (5).”
BackgroundPatricio-Martínez, A., Patricio, F., Macuil-Chapuli, E., Martínez-Juárez, E. Á., Flores-Díaz, S., Cedillo-Ramirez, M. L., & Limón, I. D. (2025) · Frontiers in Neuroscience · doi:10.3389/fnins.2025.1598011 · Cited by 23
“This process prevents the cytotoxic accumulation of A β , a hallmark of AD-associated neurodegeneration (Lee and Landreth, 2010; Wyss-Coray et al., 2003; Yoon and Jo, 2012).”
Trang, N. M., Kim, E., Pham, T. H., & Jeong, G. (2023) · Journal of Agricultural and Food Chemistry · doi:10.1021/acs.jafc.3c00368 · Cited by 21
Alzheimer’s Disease Genetics: A Dampened Microglial Response?
Chatila, Z. K., & Bradshaw, E. M. (2021) · The Neuroscientist · doi:10.1177/10738584211024531 · Cited by 20
“While innate immune cells have many roles in the CNS, impaired phagocytosis resulting in an inability to clear Aβ has long been thought to be critical to LOAD progression (Fiala and others 2005; Fiala and others 2007; Hickman and others 2008; Wildsmith and others 2013; Yoon and Jo 2012).”
BackgroundArmbrust, F., Bickenbach, K., Marengo, L., Pietrzik, C. U., & Becker‐Pauly, C. (2021) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2021.119164 · Cited by 21
Immune Response at the Crossroads of Atherosclerosis and Alzheimer's Disease
Stahr, N. A., & Galkina, E. (2022) · Frontiers in Cardiovascular Medicine · doi:10.3389/fcvm.2022.870144 · Cited by 18
Minding the Gap: Exploring Neuroinflammatory and Microglial Sex Differences in Alzheimer’s Disease
Reed-Geaghan, E. G., & Keller-Norrell, P. R. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms242417377 · Cited by 19
LeVine, S. M. (2024) · Cells · doi:10.3390/cells13080689 · Cited by 20
“Additionally, overall levels of amyloid β can increase if its clearance is decreased [23,24].”
BackgroundThe Integrative Five-Fluid Circulation System in the Human Body
Fung, P. C. W., & Kong, R. K. C. (2016) · Open Journal of Molecular and Integrative Physiology · doi:10.4236/ojmip.2016.64005 · Cited by 18
Joaquim, H. P. G., Costa, A. C., Forlenza, O. V., Gattaz, W. F., & Talib, L. L. (2019) · Archives of Clinical Psychiatry (São Paulo) · doi:10.1590/0101-60830000000209 · Cited by 18
Rodrigues‐Neves, A. C., Carecho, R., Correia, S. C., Carvalho, C., Campos, E. J., Baptista, F. I., Moreira, P. I., & Ambrósio, A. F. (2021) · Molecular Neurobiology · doi:10.1007/s12035-021-02316-x · Cited by 19
TREM2 in neurodegeneration and diseases
Abdulkhaliq, A. A., Alasiri, G., Kim, B., Khan, J., Ajoolabady, A., Yousof, S. M., Ren, J., Tuomilehto, J., Borai, A., Alrfaei, B. M., et al. (2026) · Molecular Psychiatry · doi:10.1038/s41380-026-03505-7 · Cited by 16
“These peptides are ultimately destined for removal and clearance via multiple mechanisms such as enzyme-based degradation [27].”
Autophagy in alzheimer disease pathogenesis and its therapeutic values
Angst, G., Jia, N., Esqueda, L. T., Fan, Y., Cai, Q., & Wang, C. (2025) · Autophagy Reports · doi:10.1080/27694127.2025.2471677 · Cited by 22
Experimental approaches for altering the expression of Abeta‐degrading enzymes
Loeffler, D. A. (2023) · Journal of Neurochemistry · doi:10.1111/jnc.15762 · Cited by 18
“The ability of some of these mechanisms to remove Aβ would not have been affected by the approaches which have been used in the Aβ- targeting trials performed to date (McIntee et al., 2016; Penke et al., 2017; Xin et al., 2018; Yoon & Jo, 2012).”
MethodBace1 Deletion in the Adult Reverses Epileptiform Activity and Sleep–wake Disturbances in AD Mice
Yao, A. Y., Halloran, P. J., Ge, Y., Singh, N., Zhou, J., Galske, J., He, W., Yan, R., & Hu, X. (2023) · Journal of Neuroscience · doi:10.1523/jneurosci.2124-22.2023 · Cited by 17
Zhou, L., Wei, C., Huang, W. J., Bennett, D. A., Dickson, D. W., Wang, R., & Wang, D. (2013) · Europe PMC (PubMed Central) · Cited by 16
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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