Mechanisms of Amyloid-β Peptide Clearance: Potential Therapeutic Targets for Alzheimer's Disease

Yoon, Sang-Sun; AhnJo, Sang-Mee

doi:10.4062/biomolther.2012.20.3.245

Cited by 205Alzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration MechanismsDementia and Cognitive Impairment Research

Mechanisms of Amyloid-β Peptide Clearance: Potential Therapeutic Targets for Alzheimer's Disease

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Yoon, Sang-Sun, AhnJo, Sang-Mee·2012·Biomolecules and Therapeutics

DOI 10.4062/biomolther.2012.20.3.245PMC PMC3794520

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Abstract

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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Microglia form a protective barrier to protect brain tissue from the neurotoxicity of Aβ plaques.
“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]
The “Uptake by Microglial Phagocytosis” section (page not provided) describes microglia as neuroprotective because they clear Aβ, and places them within amyloid plaques. It does not say they form a protective barrier around plaques; it also notes that activated microglia can release neurotoxic molecules. (LLM, conf=0.87)
Experimental — accuracy not yet measured
Microglia promote the clearance of Aβ aggregates.
“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]
Aβ clearance may occur through transport into cerebrospinal fluid, blood across the blood-brain barrier, and removal by brain-resident macrophages.
“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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Neprylisin decreases uniformly in Alzheimer's disease and in normal aging
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Long-term neprilysin gene transfer is associated with reduced levels of intracellular Abeta and behavioral improvement in APP transgenic mice
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In the beginning ...
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Circulating neprilysin clears brain amyloid
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Aβ42-induced Increase in Neprilysin Is Associated with Prevention of Amyloid Plaque Formation in Vivo
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Neuronal neprilysin overexpression is associated with attenuation of Aβ-related spatial memory deficit
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Inhibition of neprilysin by thiorphan (i.c.v.) causes an accumulation of amyloid β and impairment of learning and memory
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Protective effects of insulin‐like growth factor‐I on the somatostatinergic system in the temporal cortex of β‐amyloid‐treated rats
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Inhibition of Neprilysin by Infusion of Thiorphan into the Hippocampus Causes an Accumulation of Amyloid β and Impairment of Learning and Memory
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ACE variants and association with brain Aβ levels in Alzheimer's disease.
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Immunocapture-based fluorometric assay for the measurement of neprilysin-specific enzyme activity in brain tissue homogenates and cerebrospinal fluid
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JunB is a repressor of MMP-9 transcription in depolarized rat brain neurons
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NEUROLOGICAL INFECTION AND INFLAMMATION
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Yin Yang 1 Is a Critical Repressor of Matrix Metalloproteinase-9 Expression in Brain Neurons
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Notch signaling proteins HES-1 and Hey-1 bind to insulin degrading enzyme (IDE) proximal promoter and repress its transcription and activity: Implications for cellular Aβ metabolism
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Regulation by retinoic acid of insulin-degrading enzyme and of a related endoprotease in human neuroblastoma cell lines.
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Plasmin deficiency does not alter endogenous murine amyloid beta levels in mice.
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MMP‐2, ‐3 and ‐9 levels and activity are not related to Aβ load in the frontal cortex in Alzheimer's disease
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Cellular Prion Protein Participates in Amyloid-β Transcytosis across the Blood—Brain Barrier
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Effects of HNE‐modification induced by Aβ on neprilysin expression and activity in SH‐SY5Y cells
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Glutamate carboxypeptidase II: an amyloid peptide‐degrading enzyme with physiological function in the brain
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False Recognition Correlates with Amyloid-β1–42 but not with Total Tau in Cerebrospinal Fluid of Patients with Dementia and Mild Cognitive Impairment
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Accumulation of Insoluble Amyloid-β in Down's Syndrome is Associated with Increased BACE-1 and Neprilysin Activities
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Protein Kinase C-Regulated Aβ Production and Clearance
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The N‐terminal tripeptide of insulin‐like growth factor‐I protects against β‐amyloid‐induced somatostatin depletion by calcium and glycogen synthase kinase 3β modulation
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Estrogen Regulation of the Neprilysin Gene Through A Hormone-Responsive Element
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Immunocapture-based fluorometric assay for the measurement of insulin-degrading enzyme activity in brain tissue homogenates
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Association of BACE1 Gene Polymorphism with Alzheimer’s Disease in Asian Populations: Meta-Analysis Including Korean Samples
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Peroxisome Proliferator-Activated Receptor Gamma Enhances the Activity of an Insulin Degrading Enzyme-Like Metalloprotease for Amyloid-β
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160. False recognition correlates with β-amyloid (1–42), but not with total Tau in CSF of patients with dementia or mild cognitive impairment
Haldenwanger, A., & Hildebrandt, H. (2009) · Clinical Neurophysiology · doi:10.1016/j.clinph.2008.07.158 · Cited by 1 · see citing works

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[61]Love S Contribution of cerebral amyloid angiopathy to Alzheimer's disease. J. Neurol. Neurosurg. Psychiatry (2004) 75 1 4 14707293 PMC1757461

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Clearance systems in the brain—implications for Alzheimer disease
Tarasoff-Conway, J. M., Carare, R. O., Osorio, R. S., Glodzik, L., Butler, T., Fieremans, E., Axel, L., Rusinek, H., Nicholson, C., Zlokovic, B. V., et al. (2015) · Nature Reviews Neurology · doi:10.1038/nrneurol.2015.119 · Cited by 1,678 · see citing works
The Role of Amyloid-β Oligomers in Toxicity, Propagation, and Immunotherapy
Sengupta, U., Nilson, A. N., & Kayed, R. (2016) · EBioMedicine · doi:10.1016/j.ebiom.2016.03.035 · Cited by 740 · see citing works
“Therefore, any imbalance in the dynamic equilibrium maintained by these three pathways would result in the accumulation of Aβ (Yoon and Jo, 2012; Mucke, 2009).”
Background
Mechanisms of Aβ Clearance and Degradation by Glial Cells
Ries, M., & Sastre, M. (2016) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2016.00160 · Cited by 527 · see citing works
“A great number of reviews have examined the main mechanisms of Aβ clearance and degradation (Bates et al., 2009; Saido and Leissring, 2012; Yoon and Jo, 2012; Tarasoff-Conway et al., 2015).”
Background
Soluble TREM2 ameliorates pathological phenotypes by modulating microglial functions in an Alzheimer's disease model
Zhong, L., Xu, Y., Zhuo, R., Wang, T., Wang, K., Huang, R., Wang, D., Gao, Y., Zhu, Y., Sheng, X., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-09118-9 · Cited by 371 · see citing works
The Translational Significance of the Neurovascular Unit
McConnell, H. L., Kersch, C. N., Woltjer, R. L., & Neuwelt, E. A. (2017) · Journal of Biological Chemistry · doi:10.1074/jbc.r116.760215 · Cited by 314 · see citing works
Role of RAGE in Alzheimer’s Disease
Cai, Z., Liu, N., Wang, C., Qin, B., Zhou, Y., Xiao, M., Chang, L., Yan, L., & Zhao, B. (2015) · Cellular and Molecular Neurobiology · doi:10.1007/s10571-015-0233-3 · Cited by 286 · see citing works
“RAGE: The Most Important Role in the Failure of Ab Clearance Increasing research studies on Ab clearance mechanism provide new insight into the pathogenesis of AD at the molecular level which implicates that AD may result from a failure of Ab clearance in brain (Yoon and Jo 2012).”
Background
A Circadian Clock in the Blood-Brain Barrier Regulates Xenobiotic Efflux
Zhang, S., Yue, Z., Arnold, D. M., Artiushin, G., & Sehgal, A. (2018) · Cell · doi:10.1016/j.cell.2018.02.017 · Cited by 250 · see citing works
“…show increased clearance by the BBB during sleep while we demonstrate higher efflux during the day; however, their model examined an endogenous protein that is cleared largely by endocytic uptake followed by transcytosis (Yoon and Jo, 2012), rather than a xenobiotic subject to pgp-mediated efflux.”
Sleep Facilitates Clearance of Metabolites from the Brain: Glymphatic Function in Aging and Neurodegenerative Diseases
Mendelsohn, A. R., & Larrick, J. W. (2013) · Rejuvenation Research · doi:10.1089/rej.2013.1530 · Cited by 206 · see citing works
Deep cervical lymph node ligation aggravates AD‐like pathology of APP/PS1 mice
Wang, L., Zhang, Y., Zhao, Y., Marshall, C., Wu, T., & Xiao, M. (2019) · Brain Pathology · doi:10.1111/bpa.12656 · Cited by 199 · see citing works
An aging, pathology burden, and glial senescence build-up hypothesis for late onset Alzheimer’s disease
Lau, V. Z., Ramer, L. M., & Tremblay, M. (2023) · Nature Communications · doi:10.1038/s41467-023-37304-3 · Cited by 168 · see citing works
The Important Interface Between Apolipoprotein E and Neuroinflammation in Alzheimer’s Disease
Kloske, C. M., & Wilcock, D. M. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.00754 · Cited by 152 · see citing works
Therapeutic Strategies Targeting Amyloid-β in Alzheimer’s Disease
Pinheiro, L. M. V., & Faustino, C. M. C. (2019) · Current Alzheimer Research · doi:10.2174/1567205016666190321163438 · Cited by 142 · see citing works
Brain Metabolic Alterations in Alzheimer’s Disease
Ardanaz, C. G., Ramírez, M. J., & Solas, M. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23073785 · Cited by 130 · see citing works
“The degree of Aβ clearance has a great role in its accumulation [138].”
Background
Amyloid-β, tau, and the cholinergic system in Alzheimer’s disease: seeking direction in a tangle of clues
Majdi, A., Sadigh‐Eteghad, S., Aghsan, S. R., Farajdokht, F., Vatandoust, S. M., Abbas-Abad, A. N., & Mahmoudi, J. (2020) · Reviews in the Neurosciences · doi:10.1515/revneuro-2019-0089 · Cited by 124 · see citing works
Modeling the Role of the Glymphatic Pathway and Cerebral Blood Vessel Properties in Alzheimer’s Disease Pathogenesis
Kyrtsos, C. R., & Baras, J. S. (2015) · PLoS ONE · doi:10.1371/journal.pone.0139574 · Cited by 106 · see citing works
Inflammatory Cascade in Alzheimer’s Disease Pathogenesis: A Review of Experimental Findings
de Oliveira, J., Kucharska, E., Garcez, M. L., Rodrigues, M. S., Quevedo, J., Moreno‐González, I., & Budni, J. (2021) · Cells · doi:10.3390/cells10102581 · Cited by 105 · see citing works
“The clearance of the peptide by transport into the cerebrospinal fluid (CSF), the blood across the blood–brain barrier (BBB), and the removal by macrophages have been suggested as the responsible mechanisms for controlling the brain Aβ levels [27].”
Alzheimer’s disease as type 3 diabetes: understanding the link and implications
Kciuk, M., Kruczkowska, W., Gałęziewska, J., Wanke, K., Kałuzińska-Kołat, Ż., Aleksandrowicz, M., & Kontek, R. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms252211955 · Cited by 98 · see citing works
“Although A β protein is normally present in synapses within the CNS, pathological circumstances lead to its increased deposition in regions like the frontal cortex and hippocampus [125].”
Neuroprotective effects of a biodegradable poly(lactic-co-glycolic acid)-ginsenoside Rg3 nanoformulation: a potential nanotherapy for Alzheimer’s disease?
Aalinkeel, R., Kutscher, H. L., Singh, A. K., Cwiklinski, K., Khechen, N., Schwartz, S. A., Prasad, P. N., & Mahajan, S. D. (2017) · Journal of drug targeting · doi:10.1080/1061186x.2017.1354002 · Cited by 97 · see citing works
P‐glycoprotein: a role in the export of amyloid‐β in Alzheimer's disease?
Chai, A. B., Leung, G. K. F., Callaghan, R., & Gelissen, I. C. (2019) · FEBS Journal · doi:10.1111/febs.15148 · Cited by 98 · see citing works
Sleep, Cognition and Dementia
Porter, V. R., Buxton, W. G., & Avidan, A. Y. (2015) · Current Psychiatry Reports · doi:10.1007/s11920-015-0631-8 · Cited by 94 · see citing works
Resveratrol and Amyloid-Beta: Mechanistic Insights
Jia, Y., Wang, N., & Liu, X. (2017) · Nutrients · doi:10.3390/nu9101122 · Cited by 91 · see citing works
“Metabolic pathway of Aβ in AD pathogenesis, especially in late-onset sporadic AD (LOAD) has been raised, and the main mechanisms of Aβ clearance have been considered as new therapeutic targets [51,52].”
Background
Impact of Insulin Degrading Enzyme and Neprilysin in Alzheimer’s Disease Biology: Characterization of Putative Cognates for Therapeutic Applications
Jha, N. K., Jha, S., Kumar, D., Kejriwal, N., Sharma, R., Ambasta, R. K., & Kumar, P. (2015) · Journal of Alzheimer's Disease · doi:10.3233/jad-150379 · Cited by 79 · see citing works
Peripheral Glycolysis in Neurodegenerative Diseases
Bell, S., Burgess, T., Lee, J., Blackburn, D. J., Allen, S. P., & Mortiboys, H. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21238924 · Cited by 83 · see citing works
“This has led to the interpretation that increased glycolytic enzyme activity in RBC in AD results from an increased demand for ATP generated through glycolysis to maintain the Na/K-ATPase pump [36,37].”
Background
Abnormal amyloid beta metabolism in systemic abnormalities and Alzheimer’s pathology: Insights and therapeutic approaches from periphery
Ullah, R., Park, T. J., Huang, X., & Kim, M. O. (2021) · Ageing Research Reviews · doi:10.1016/j.arr.2021.101451 · Cited by 78 · see citing works
The Dynamic Relationship between the Glymphatic System, Aging, Memory, and Sleep
Voumvourakis, K. I., Sideri, E., Papadimitropoulos, G. N., Tsantzali, I., Hewlett, P., Kitsos, D. K., Stefanou, M., Bonakis, A., Giannopoulos, S., Tsivgoulis, G., et al. (2023) · Biomedicines · doi:10.3390/biomedicines11082092 · Cited by 79 · see citing works
Exploring the Therapeutic Potential of Phytochemicals in Alzheimer’s Disease: Focus on Polyphenols and Monoterpenes
Piccialli, I., Tedeschi, V., Caputo, L., D’Errico, S., Ciccone, R., De Feo, V., Secondo, A., & Pannaccione, A. (2022) · Frontiers in Pharmacology · doi:10.3389/fphar.2022.876614 · Cited by 73 · see citing works
“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).”
Background
The Positive Side of the Alzheimer’s Disease Amyloid Cross-Interactions: The Case of the Aβ 1-42 Peptide with Tau, TTR, CysC, and ApoA1
Ciccone, L., Shi, C., di Lorenzo, D., Van Baelen, A.-C., & Tonali, N. (2020) · Molecules · doi:10.3390/molecules25102439 · Cited by 69 · see citing works
“Overall impairment in Aβ clearance is also a major contributor to disease development [13].”
Background
Acoustofluidic assembly of 3D neurospheroids to model Alzheimer's disease
Cai, H., Ao, Z., Hu, L., Moon, Y., Wu, Z., Lu, H.-C., Kim, J., & Guo, F. (2020) · The Analyst · doi:10.1039/d0an01373k · Cited by 70 · see citing works
Autophagy Modulation as a Treatment of Amyloid Diseases
Mputhia, Z., Hone, E., Tripathi, T., Sargeant, T. J., Martins, R. N., & Bharadwaj, P. (2019) · Molecules · doi:10.3390/molecules24183372 · Cited by 69 · see citing works
Andrographolide Activates Keap1/Nrf2/ARE/HO-1 Pathway in HT22 Cells and Suppresses Microglial Activation by Aβ42through Nrf2-Related Inflammatory Response
Seo, J. Y., Pyo, E., An, J., Kim, J., Sung, S. H., & Oh, W. K. (2017) · Mediators of Inflammation · doi:10.1155/2017/5906189 · Cited by 70 · see citing works
“For example, glutamate carboxypeptidase II, matrix metalloproteinase 9, and insulin-degrading enzyme are closely associated with Aβ peptide clearance [24].”
Background
Myelin in Alzheimer’s disease: culprit or bystander?
Maitre, M., Jeltsch-David, H., Okechukwu, N. G., Klein, C., Patte-Mensah, C., & Mensah-Nyagan, A.-G. (2023) · Acta Neuropathologica Communications · doi:10.1186/s40478-023-01554-5 · Cited by 66 · see citing works
Targeting of ECM molecules and their metabolizing enzymes and receptors for the treatment of CNS diseases
Berezin, V., Walmod, P. S., Filippov, M. A., & Dityatev, A. E. (2014) · Progress in brain research · doi:10.1016/b978-0-444-63486-3.00015-3 · Cited by 62 · see citing works
Aluminum chloride-induced amyloid β accumulation and endoplasmic reticulum stress in rat brain are averted by melatonin
Promyo, K., Iqbal, F., Chaidee, N., & Chetsawang, B. (2020) · Food and Chemical Toxicology · doi:10.1016/j.fct.2020.111829 · Cited by 63 · see citing works
Inflammation as common link to progressive neurological diseases
Dias-Carvalho, A., Sá, S. I., Carvalho, F., Fernandes, E., & Costa, V. M. (2024) · Archives of Toxicology · doi:10.1007/s00204-023-03628-8 · Cited by 60 · see citing works
“Nonetheless, the imbalance in the APP processing pathways that increase Aβ production and decrease the mechanisms of clearance, results in Aβ accumulation and consequential plaque formation (Yoon and Jo 2012).”
Background
Cerebral Amyloid Angiopathy and Blood-Brain Barrier Dysfunction
Gireud, M., Mack, A. F., McCullough, L. D., & Urayama, A. (2020) · The Neuroscientist · doi:10.1177/1073858420954811 · Cited by 61 · see citing works
Spinosin, a C-Glucosylflavone, from Zizyphus jujuba var. spinosa Ameliorates Aβ1–42 Oligomer-Induced Memory Impairment in Mice
Ko, S. Y., Lee, H. E., Park, S. J., Jeon, S. J., Kim, B., Gao, Q., Jang, D. S., & Ryu, J. H. (2015) · Biomolecules & Therapeutics · doi:10.4062/biomolther.2014.110 · Cited by 59 · see citing works
“Although previous studies have been focused on unveiling AD pathology and reducing the symptoms of this disease by clearing Ab protein, this methodology has been unsuccessful (Yoon and Jo, 2012; Chiang and Koo, 2014).”
Aβ promotes CD38 expression in senescent microglia in Alzheimer’s disease
Hu, Y., Huang, Y., Xing, S., Chen, C., Shen, D., & Chen, J. (2022) · Biological Research · doi:10.1186/s40659-022-00379-1 · Cited by 55 · see citing works
“As immune cells in the central nervous system, microglia play a key role in brain development and immune defense and can also clear Aβ deposition [8].”
Background
Icariside II, a Broad-Spectrum Anti-cancer Agent, Reverses Beta-Amyloid-Induced Cognitive Impairment through Reducing Inflammation and Apoptosis in Rats
Deng, Y., Long, L., Wang, K., Zhou, J., Zeng, L., He, L., & Gong, Q. (2017) · Frontiers in Pharmacology · doi:10.3389/fphar.2017.00039 · Cited by 55 · see citing works
“ICS II Alleviated Aβ-Induced Spatial”
Effects of fermented ginseng on memory impairment and β-amyloid reduction in Alzheimer's disease experimental models
Kim, J., Kim, S. H., Lee, D.-S., Lee, D., Kim, S.-H., Chung, S., & Yang, H. O. (2013) · Journal of Ginseng Research · doi:10.5142/jgr.2013.37.100 · Cited by 52 · see citing works
Effect of conjugated linoleic acid, μ-calpain inhibitor, on pathogenesis of Alzheimer's disease
Lee, E., Eom, J.-E., Kim, H.-L., Baek, K. H., Jun, K.-Y., Kim, H., Lee, M., Mook‐Jung, I., & Kwon, Y. (2012) · Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids · doi:10.1016/j.bbalip.2012.12.003 · Cited by 50 · see citing works
Advances in Amyloid-β Clearance in the Brain and Periphery: Implications for Neurodegenerative Diseases
Ullah, R., & Lee, E. J. (2023) · Experimental Neurobiology · doi:10.5607/en23014 · Cited by 46 · see citing works
“In the brain, both intracellular and extracellular amyloid-β are primarily degraded and cleared through the proteolytic machinery [40, 43].”
BackgroundInfluential
Gut Microbiota Metabolite Messengers in Brain Function and Pathology at a View of Cell Type-Based Receptor and Enzyme Reaction
Lee, B., Lee, S. M., Song, J. W., & Choi, J. W. (2024) · Biomolecules & Therapeutics · doi:10.4062/biomolther.2024.009 · Cited by 48 · see citing works
Aβ1-42 induces cell damage via RAGE-dependent endoplasmic reticulum stress in bEnd.3 cells
Chen, W., Chan, Y., Wan, W., Li, Y., & Zhang, C. (2017) · Experimental Cell Research · doi:10.1016/j.yexcr.2017.11.005 · Cited by 47 · see citing works
Microglial Turnover in Ageing-Related Neurodegeneration: Therapeutic Avenue to Intervene in Disease Progression
Azam, S., Haque, M. E., Kim, I., & Choi, D. (2021) · Cells · doi:10.3390/cells10010150 · Cited by 45 · see citing works
“Therefore, microglial scavenger receptors (SRs) have an active role in Aβ clearance [65] by phagocytosis and endocytosis [66,67].”
Background
Reduction of amyloid-beta levels in mouse eye tissues by intra-vitreally delivered neprilysin
Parthasarathy, R., Chow, K. M., Derafshi, Z., Fautsch, M. P., Hetling, J. R., Rodgers, D. W., Hersh, L. B., & Pepperberg, D. R. (2015) · Experimental Eye Research · doi:10.1016/j.exer.2015.06.027 · Cited by 44 · see citing works
“…Nalivaeva et al., 2012; Wildsmith et al., 2013), but that, upon the marked decrease in Aβ induced by sNEP treatment, endogenous Aβ degradation/ clearance processes (Saido and Leissring, 2012; Tanzi et al., 2004; Yoon and Jo, 2012) become able to maintain Aβ at relatively low levels for many weeks.”
Background
Effect of growth differentiation factor-15 secreted by human umbilical cord blood-derived mesenchymal stem cells on amyloid beta levels in in vitro and in vivo models of Alzheimer's disease
Kim, D. H., Lee, D., Lim, H., Choi, S. J., Oh, W., Yang, Y. S., Chang, J. H., & Jeon, H. B. (2018) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2018.09.012 · Cited by 44 · see citing works
DSCR1 upregulation enhances dural meningeal lymphatic drainage to attenuate amyloid pathology of A lzheimer's disease
Choi, C., Park, J. W., Kim, H., Chang, K. T., Park, J., & Min, K. (2021) · The Journal of Pathology · doi:10.1002/path.5767 · Cited by 44 · see citing works
Protein levels of ADAM10, BACE1, and PSEN1 in platelets and leukocytes of Alzheimer’s disease patients
Bram, J. M. D. F., Talib, L. L., Joaquim, H. P. G., Sarno, T. A., Gattaz, W. F., & Forlenza, O. V. (2018) · European Archives of Psychiatry and Clinical Neuroscience · doi:10.1007/s00406-018-0905-3 · Cited by 43 · see citing works
Fungicide Residues Exposure and β-amyloid Aggregation in a Mouse Model of Alzheimer’s Disease
Lafon, P., Wang, Y., Arango-Lievano, M., Torrent, J., Salvador-Prince, L., Mansuy, M., Mestre‐Francés, N., Givalois, L., Liu, J., Mercader, J. V., et al. (2020) · Environmental Health Perspectives · doi:10.1289/ehp5550 · Cited by 43 · see citing works
Neuroprotective Effects of Spinosin on Recovery of Learning and Memory in a Mouse Model of Alzheimer’s Disease
Xu, F., He, B., Feng, X., Yan, T., Bi, K., Jia, Y., & Wang, Z. (2018) · Biomolecules & Therapeutics · doi:10.4062/biomolther.2018.051 · Cited by 42 · see citing works
“AD is characterized by the over-production of amyloid-beta (Aβ), which is regarded as one of the essential pathologic markers of AD (Yoon and Jo, 2012).”
Background
Employing nanoparticle tracking analysis of salivary neuronal exosomes for early detection of neurodegenerative diseases
Sharma, V., Nikolajeff, F. K., & Kumar, S. (2023) · Translational Neurodegeneration · doi:10.1186/s40035-023-00339-z · Cited by 41 · see citing works
“These senile amyloid plaques result from either overproduction of Aβ (~ 1% in familial forms) or dysfunction of Aβ clearance, which is hypothesized to be the main cause of Aβ accumulation in sporadic AD that accounts for 99% of total AD cases [6, 7].”
Background
Protopanaxadiol derivative DDPU improves behavior and cognitive deficit in AD mice involving regulation of both ER stress and autophagy
Guo, X., Lv, J., Lu, J., Fan, L., Huang, X., Hu, L., Wang, J., & Shen, X. (2017) · Neuropharmacology · doi:10.1016/j.neuropharm.2017.11.033 · Cited by 41 · see citing works
Brain targeting based nanocarriers loaded with resveratrol in Alzheimer's disease: A review
Jalili, C., Kiani, A., Gholami, M., Bahrehmand, F., Fakhri, S., Kakehbaraei, S., & Kakebaraei, S. (2023) · IET Nanobiotechnology · doi:10.1049/nbt2.12127 · Cited by 42 · see citing works
“Findings have indicated the presence of inflammatory biomarkers in the adult brain with AD, for example, enhancing the proinflammatory cytokines/chemokines in cerebrospinal fluid (CSF) and serum, along with symptoms of micro gliosis [85].”
Background
Deleterious Alteration of Glia in the Brain of Alzheimer’s Disease
Kim, E., Otgontenger, U., Jamsranjav, A., & Kim, S. S. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21186676 · Cited by 41 · see citing works
“After decades of research, however, most AD therapy candidates have failed to revert the symptom, even though they can faithfully remove Aβ plaque accumulation in the cortex [5].”
Background
The Potential Role of Herpes Simplex Virus Type 1 and Neuroinflammation in the Pathogenesis of Alzheimer's Disease
Laval, K., & Enquist, L. W. (2021) · Frontiers in Neurology · doi:10.3389/fneur.2021.658695 · Cited by 40 · see citing works
“What Doesn’t Kill You Makes You Stronger”: Future Applications of Amyloid Aggregates in Biomedicine
Abdelrahman, S., Alghrably, M., Lachowicz, J. I., Emwas, A.-H. M., Hauser, C. A. E., & Jaremko, M. (2020) · Molecules · doi:10.3390/molecules25225245 · Cited by 38 · see citing works
“Several protease enzymes are involved in the enzymatic clearance mechanism [223].”
BackgroundInfluential
Ketone bodies mediate alterations in brain energy metabolism and biomarkers of Alzheimer’s disease
Ramezani, M., Fernando, M. G., Eslick, S., Asih, P. R., Shadfar, S., Bandara, E. M. S., Hillebrandt, H., Meghwar, S., Shahriari, M., Chatterjee, P., et al. (2023) · Frontiers in Neuroscience · doi:10.3389/fnins.2023.1297984 · Cited by 38 · see citing works
Periodontitis Deteriorates Cognitive Function and Impairs Neurons and Glia in a Mouse Model of Alzheimer’s Disease
Qian, X., Zhang, S., Duan, L., Yang, F., Zhang, K., Yan, F., & Ge, S. (2021) · Journal of Alzheimer s Disease · doi:10.3233/jad-201007 · Cited by 38 · see citing works
“A (cid:2) , which is generated during A (cid:2) PP metabolism, is cleared via enzymatic degradation pathways [55, 56].”
Phagocytic Glial Cells in Brain Homeostasis
Kono, R., Ikegaya, Y., & Koyama, R. (2021) · Cells · doi:10.3390/cells10061348 · Cited by 37 · see citing works
“Since Aβ deposition is often observed in the brains of Alzheimer’s disease (AD) patients, the Aβ clearance pathway has been presumed to be a therapeutic target for AD, and efforts have been focused on revealing Aβ clearance mechanisms [27].”
Background
Degradation of Bone Quality in a Transgenic Mouse Model of Alzheimer′s Disease
LLabre, J. E., Gil, C., Amatya, N., Lagalwar, S., Possidente, B. P., & Vashishth, D. (2020) · Journal of Bone and Mineral Research · doi:10.1002/jbmr.4723 · Cited by 35 · see citing works
“Interestingly, Aβ can interfere with the RANK downstream signaling((34)) and stimulate osteoclast-specific genes.”
Background
Benzimidazole-derived Compounds Designed for Different Targets of Alzheimer’s Disease
Gülcan, H. O., Mavideniz, A., Sahin, M. F., & Orhan, İ. E. (2019) · Current Medicinal Chemistry · doi:10.2174/0929867326666190124123208 · Cited by 35 · see citing works
Suppression of Alzheimer's disease‑related phenotypes by the heat shock protein 70 inducer, geranylgeranylacetone, in APP/PS1 transgenic mice via the ERK/p38 MAPK signaling pathway
Sun, Y., Zhang, J., & Chen, S. (2017) · Experimental and Therapeutic Medicine · doi:10.3892/etm.2017.5253 · Cited by 34 · see citing works
“Previous studies have suggested different mechanisms for the removal of A β from the brain (8,9).”
Dissecting Endoplasmic Reticulum Unfolded Protein Response (UPRER) in Managing Clandestine Modus Operandi of Alzheimer’s Disease
Rahman, S., Ayyagari, A., Jan, A. T., & Minakshi, R. (2018) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2018.00030 · Cited by 31 · see citing works
“The JNK3 (member of JNK family) localized in brain, is highly expressed in brain tissue and cerebrospinal fluid sample from AD patients (Gourmaud et al., 2015) and the activation of JNK3 exacerbates stress perpetuating AD pathology (Yoon and Jo, 2012).”
Background
Chronic Rhinosinusitis and Alzheimer’s Disease—A Possible Role for the Nasal Microbiome in Causing Neurodegeneration in the Elderly
Harrass, S., Yi, C., & Chen, H. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms222011207 · Cited by 31 · see citing works
“Nowadays, studies on AD still place Aβ as an important target for investigation; however, the failure to develop a drug has undermined the Aβ-based therapeutic approaches [65,66].”
Background
Based on molecular structures: Amyloid-β generation, clearance, toxicity and therapeutic strategies
Yang, H., Li, J., Li, X., Ma, L., Hou, M., Zhou, H., & Zhou, R. (2022) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2022.927530 · Cited by 30 · see citing works
Neuroprotective Activities of Heparin, Heparinase III, and Hyaluronic Acid on the Aβ42-Treated Forebrain Spheroids Derived from Human Stem Cells
Bejoy, J., Song, L., Wang, Z., Sang, Q., Zhou, Y., & Li, Y. (2018) · ACS Biomaterials Science & Engineering · doi:10.1021/acsbiomaterials.8b00021 · Cited by 27 · see citing works
Repellent Effects of Selected Organic Leaf Extracts of Tithonia diversifolia (Hemsl.) A. Gray and Vernonia lasiopus (O. Hoffman) against Sitophilus zeamais Motschulsky (Coleoptera: Curculionidae)
Gitahi, S. M., Ngugi, M. P., Mburu, D., & Machocho, A. K. (2021) · The Scientific World JOURNAL · doi:10.1155/2021/2718629 · Cited by 29 · see citing works
“Likewise, Yoon and Ahnjo [35] also reported that caraway and grapefruit successfully repelled weevils at such high rates.”
Background
Fragment-based drug discovery for disorders of the central nervous system: designing better drugs piece by piece
Chan, B. W. G. L., Lynch, N. B., Tran, W., Joyce, J. M., Savage, G. P., Meutermans, W. D. F., Montgomery, A. P., & Kassiou, M. (2024) · Frontiers in Chemistry · doi:10.3389/fchem.2024.1379518 · Cited by 28 · see citing works
Role of Mitochondrial Dysfunction in the Pathology of Amyloid-β
Huang, Z., Yan, Q., Wang, Y., Zou, Q., Li, J., Liu, Z., & Cai, Z. (2020) · Journal of Alzheimer s Disease · doi:10.3233/jad-200519 · Cited by 28 · see citing works
Neutral Endopeptidase (Neprilysin) in Therapy and Diagnostics: Yin and Yang
Feygina, E. E., Katrukha, A., & Semenov, A. G. (2019) · Biochemistry (Moscow) · doi:10.1134/s0006297919110105 · Cited by 21 · see citing works
The roles of long non-coding RNAs in Alzheimer's disease diagnosis, treatment, and their involvement in Alzheimer's disease immune responses
Wu, X., Xia, P., Yang, L., Lü, C., & Lu, Z. (2024) · Non-coding RNA Research · doi:10.1016/j.ncrna.2024.03.008 · Cited by 26 · see citing works
“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].”
Background
Beyond 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 28 · see citing works
“…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].”
Background
Amyloid 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 25 · see citing works
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 · see citing works
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 · see citing works
The immunomodulatory effects of mesenchymal stem cell-derived extracellular vesicles in Alzheimer's disease
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 26 · see citing works
Neprilysin-Mediated Amyloid Beta Clearance and Its Therapeutic Implications in Neurodegenerative Disorders
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 24 · see citing works
The potential value of capsaicin in modulating cognitive functions in a rat model of streptozotocin-induced Alzheimer’s disease
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 · see citing works
Comparison of Oleocanthal-Low EVOO and Oleocanthal against Amyloid-β and Related Pathology in a Mouse Model of Alzheimer’s Disease
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 24 · see citing works
“In the initial stages of AD, glial cells positively affect Aβ elimination by phagocytosis [15].”
Background
Comparison 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 · see citing works
The Neuroprotective Effects of Justicidin A on Amyloid Beta25–35-Induced Neuronal Cell Death Through Inhibition of Tau Hyperphosphorylation and Induction of Autophagy in SH-SY5Y Cells
Gu, M.-Y., Kim, J., & Yang, H.-O. (2016) · Neurochemical Research · doi:10.1007/s11064-016-1857-5 · Cited by 22 · see citing works
Progranulin Administration Attenuates β-Amyloid Deposition in the Hippocampus of 5xFAD Mice Through Modulating BACE1 Expression and Microglial Phagocytosis
Guan, Z., Chen, Z., Fu, S., Dai, L., & Shen, Y. (2020) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2020.00260 · Cited by 21 · see citing works
“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).”
Background
Multiple Roles of Apolipoprotein E4 in Oxidative Lipid Metabolism and Ferroptosis During the Pathogenesis of Alzheimer’s Disease
Faraji, P., Kühn, H., & Ahmadian, S. (2024) · Journal of Molecular Neuroscience · doi:10.1007/s12031-024-02224-4 · Cited by 23 · see citing works
Intracranial Arterial 4D Flow in Individuals with Mild Cognitive Impairment is Associated with Cognitive Performance and Amyloid Positivity
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 · see citing works
Amyloid beta-protein and lipid rafts focused on biogenesis and catabolism
Araki, W. (2015) · Frontiers in bioscience · doi:10.2741/4311 · Cited by 21 · see citing works
“Aβ clearance is additionally mediated by microglial phagocytosis (5).”
Background
The role of probiotics, prebiotics, and postbiotics: cellular and molecular pathways activated on glial cells in Alzheimer’s disease
Patricio-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 22 · see citing works
“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).”
Citropten Ameliorates Osteoclastogenesis Related to MAPK and PLCγ/Ca2+ Signaling Pathways through the Regulation of Amyloid Beta
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 20 · see citing works
Alzheimer’s Disease Genetics: A Dampened Microglial Response?
Chatila, Z. K., & Bradshaw, E. M. (2021) · The Neuroscientist · doi:10.1177/10738584211024531 · Cited by 20 · see citing works
“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).”
Background
The Swedish dilemma - the almost exclusive use of APPswe-based mouse models impedes adequate evaluation of alternative β-secretases
Armbrust, 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 20 · see citing works
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 · see citing works
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 · see citing works
Exploring Potential Mechanisms Accounting for Iron Accumulation in the Central Nervous System of Patients with Alzheimer’s Disease
LeVine, S. M. (2024) · Cells · doi:10.3390/cells13080689 · Cited by 17 · see citing works
“Additionally, overall levels of amyloid β can increase if its clearance is decreased [23,24].”
Background
The Integrative Five-Fluid Circulation System in the Human Body
Fung, P., & Kong, R. K. (2016) · Open Journal of Molecular and Integrative Physiology · doi:10.4236/ojmip.2016.64005 · Cited by 15 · see citing works
Decreased plasmatic spermidine and increased spermine in mild cognitive impairment and Alzheimer’s disease patients
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 · see citing works
Retina and Brain Display Early and Differential Molecular and Cellular Changes in the 3xTg-AD Mouse Model of Alzheimer’s Disease
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 18 · see citing works
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 · see citing works
“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 19 · see citing works
Experimental approaches for altering the expression of Abeta‐degrading enzymes
Loeffler, D. A. (2023) · Journal of Neurochemistry · doi:10.1111/jnc.15762 · Cited by 17 · see citing works
“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).”
Method
Bace1 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 21 · see citing works
Distinct subcellular patterns of neprilysin protein and activity in the brains of Alzheimer's disease patients, transgenic mice and cultured human neuronal cells.
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 · see citing works

Authors: Yoon, S.-S., & AhnJo, S.-M.
Affiliations: Dankook University (KR)
ORCID: Yoon, Sang-Sun
Venue: Biomolecules and Therapeutics
Publisher: The Korean Society of Applied Pharmacology
Published: 2012-05-31
Volume: 20
Issue: 3
Pages: 245-255
ISSN: 1976-9148 (ISSN-L)
DOI: 10.4062/biomolther.2012.20.3.245
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: Health Sciences › Medicine › Physiology › 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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Mechanisms of Amyloid-β Peptide Clearance: Potential Therapeutic Targets for Alzheimer's Disease

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