The DOI matches its Crossref record; 119 of the 122 references it cites were found in a registry or an index.
Mechanisms of Aβ Clearance and Degradation by Glial Cells
Open accessAbstract
Glial cells have a variety of functions in the brain, ranging from immune defense against external and endogenous hazardous stimuli, regulation of synaptic formation, calcium homeostasis, and metabolic support for neurons. Their dysregulation can contribute to the development of neurodegenerative disorders, including Alzheimer's disease (AD). One of the most important functions of glial cells in AD is the regulation of Amyloid-β (Aβ) levels in the brain. Microglia and astrocytes have been reported to play a central role as moderators of Aβ clearance and degradation. The mechanisms of Aβ degradation by glial cells include the production of proteases, including neprilysin, the insulin degrading enzyme, and the endothelin-converting enzymes, able to hydrolyse Aβ at different cleavage sites. Besides these enzymes, other proteases have been described to have some role in Aβ elimination, such as plasminogen activators, angiotensin-converting enzyme, and matrix metalloproteinases. Other relevant mediators that are released by glial cells are extracellular chaperones, involved in the clearance of Aβ alone or in association with receptors/transporters that facilitate their exit to the blood circulation. These include apolipoproteins, α2macroglobulin, and α1-antichymotrypsin. Finally, astrocytes and microglia have an essential role in phagocytosing Aβ, in many cases via a number of receptors that are expressed on their surface. In this review, we examine all of these mechanisms, providing an update on the latest research in this field.
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“Microglia activation reduces the accumulation of Aβ in the brain by increasing its phagocytosis, clearance, and degradation75.”
From Chlamydia pneumoniae can infect the central nervous system via the olfactory and trigeminal nerves and contributes to Alzheimer’s disease risk (2022) · cites this paper as [75]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
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“The secretion of Aβ may thus be a normal immune response to any microbe that may invade the nervous system, and if infection clears, the deposited Aβ can be cleared by phagocytic glia71.”
From Chlamydia pneumoniae can infect the central nervous system via the olfactory and trigeminal nerves and contributes to Alzheimer’s disease risk (2022) · cites this paper as [71]
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In the citing paper
“Astrocytes can produce Aβ peptidases, such as neprilysin and IDE as well as the Apolipoprotein E (ApoE) [15]”
From Pharmacological ablation of astrocytes reduces Aβ degradation and synaptic connectivity in an ex vivo model of Alzheimer’s disease (2021) · cites this paper as [15]
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“Neprilysin is mainly expressed in neurons [32] but can also be found in activated astrocytes and microglia [15]”
From Pharmacological ablation of astrocytes reduces Aβ degradation and synaptic connectivity in an ex vivo model of Alzheimer’s disease (2021) · cites this paper as [15]
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“ApoE is mainly produced in astrocytes but can be synthesized by microglia [15].”
From Pharmacological ablation of astrocytes reduces Aβ degradation and synaptic connectivity in an ex vivo model of Alzheimer’s disease (2021) · cites this paper as [15]
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“Indeed, microglia and astrocytes have been shown to play a key role in Aβ clearance and degradation [92].”
From Senescence-related impairment of autophagy induces toxic intraneuronal amyloid-β accumulation in a mouse model of amyloid pathology (2023) · cites this paper as [92]
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Citations
Cites
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“IDE is unequally expressed in human brain, majorly found in hypothalamic neurons and in hippocampus, cerebellum, and brain stem (Bernstein et al., 2008), coinciding with the location of insulin receptors in the brain.”
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“The uptake and degradation of insoluble A β , comprised of neurotoxic, soluble A β oligomers, occur through different endocytic mechanisms that are microglia and astrocytic receptor mediated (186–188).”
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“However, the impact of LD-RT seems to be more complex: a recent study observed only a reduction of plaque size by not of the total plaque number in the 5xFAD mouse model [16], suggesting a slow mechanism of degradation, maybe by neighboring glial cells [30].”
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“Although glial cells are considered to be primarily responsible for uptake and clearance of amyloid-β [22, 78], our results open the possibility that LPL may have glial cell-independent effects on amyloid reduction, warranting further analysis.”
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“Astrocytes can produce Aβ-degrading proteases, such as insulin-degrading enzyme, metalloendopeptidases neprilysin, and endothelin-converting enzymes 1 and 2, which cleave the peptide into smaller fragments (Ries and Sastre, 2016).”
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Connexin 43 Controls the Astrocyte Immunoregulatory Phenotype
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“Indeed, astrocytes have been shown to take up tau (Perea et al., 2019), Aβ (Ries and Sastre, 2016), and α-synuclein (Lee et al., 2010), although there is disagreement as to whether this primarily serves a neuroprotective or a pathogenic function.”
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“It has been verified that insulin can penetrate the blood-brain barrier (BBB) through a transporter, consequently regulating the relevant information transmission pathways in the brain (Derakhshan and Toth, 2013).”
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“In the CNS, NEP is mostly present in pre-synaptic neuronal termini, but can also be detected in activated astrocytes and microglia (Ries and Sastre, 2016).”
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“Neprilysin inhibitors tend to inhibit Aβ degradation, leading to imbalance between production and clearance of Aβ with increased Aβ accumulation [6, 7].”
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APOE4 impairs autophagy and Aβ clearance by microglial cells
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Mechanistic insights regarding neuropsychiatric and neuropathologic impacts of air pollution
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“Microglia are the resident macrophages of the brain parenchyma and are vital for promoting proteasomal and lysosomal clearance of pathogens and foreign bodies (Shibuya et al. 2014; Ries and Sastre 2016).”
Cyclical amyloid beta-astrocyte activity induces oxidative stress in Alzheimer’s disease
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GPR120 Signaling Controls Amyloid-β Degrading Activity of Matrix Metalloproteinases
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RETRACTED ARTICLE: Exploring the Role of CLU in the Pathogenesis of Alzheimer’s Disease
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Pathology of Amyloid-β (Aβ) Peptide Peripheral Clearance in Alzheimer’s Disease
Tsoy, A., Umbayev, B. A., Kassenova, A., Kaupbayeva, B., & Askarova, S. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms252010964 · Cited by 24
Chen, F., Fang, S., Du, Y., Ghosh, A., Reed, M. N., Long, Y., Suppiramaniam, V. D., Tang, S., & Hong, H. (2021) · Aging · doi:10.18632/aging.202501 · Cited by 21
“Furthermore, the proteolytic enzymes, IDE and NEP, that degrade Aβ were not altered significantly by CysLT1R gene knockout or knockdown [25].”
BackgroundYang, L., Chen, Z., Wan, X., Liu, M., Wu, J., Chen, Y., Zhang, G., & Fan, Z. (2021) · International Journal of Neuroscience · doi:10.1080/00207454.2021.1946056 · Cited by 21
“During chronic dysfunction of GS, damage of these glial cells may result in the decrease of clearance ability and increase of Aβ [10].”
BackgroundKim, J., Lim, D.-K., Suh, Y., & Chang, K. (2021) · Antioxidants · doi:10.3390/antiox10081321 · Cited by 20
Yang, C., & Xu, P. (2022) · Molecular Biology Reports · doi:10.1007/s11033-022-07951-8 · Cited by 22
Means, J. C., Lopez, A. A., & Koulen, P. (2020) · Cellular and Molecular Neurobiology · doi:10.1007/s10571-020-00859-6 · Cited by 20
Yamamoto, N., Nakazawa, M., Nunono, N., Yoshida, N., Obuchi, A., Tanida, M., Suzuki, K., Ikeda‐Matsuo, Y., & Sobue, K. (2020) · Neuroscience Research · doi:10.1016/j.neures.2020.05.008 · Cited by 20
Tang, M.-Y., Gorin, F. A., & Lein, P. J. (2022) · Ageing and Neurodegenerative Diseases · doi:10.20517/and.2022.05 · Cited by 20
“While microglial phagocytosis of amyloid may be neuroprotective in the early stages of AD by promoting Aβ clearance[20,21], microglial activation in later stages may promote the progression of AD[1,16].”
BackgroundPatients with Alzheimer’s disease have an increased removal rate of soluble beta-amyloid-42
Zaretsky, D. V., Zaretskaia, M. V., Molkov, Y. I., & Initiative, A. D. N. (2022) · PLoS ONE · doi:10.1371/journal.pone.0276933 · Cited by 23
“The degradation of beta-amyloid is mediated by proteases [55].”
BackgroundThe Hidden Role of Non-Canonical Amyloid β Isoforms in Alzheimer’s Disease
Busch, L., Eggert, S., Endres, K., & Bufe, B. (2022) · Cells · doi:10.3390/cells11213421 · Cited by 20
Proust, A. M., Barat, C., Lebœuf, M., Drouin, J., Gagnon, M., Vanasse, F., & Tremblay, M. J. (2020) · Glia · doi:10.1002/glia.23833 · Cited by 19
Bai, Y., & Ma, X. (2020) · International Immunopharmacology · doi:10.1016/j.intimp.2020.106790 · Cited by 21
Tsukahara, T., Haniu, H., Uemura, T., & Matsuda, Y. (2020) · Biomedicines · doi:10.3390/biomedicines8110446 · Cited by 20
Impact of New Drugs for Therapeutic Intervention in Alzheimer’s Disease
Olloquequi, J., Ettcheto, M., Cano, A. C., Sánchez‐López, E., Carrasco, M., Espinosa-Jiménez, T., Beas‐Zárate, C., Gudiño‐Cabrera, G., Ureña‐Guerrero, M. E., Verdaguer, E., et al. (2022) · Frontiers in Bioscience-Landmark · doi:10.31083/j.fbl2705146 · Cited by 25
“After binding to receptors, microglia cells also endocyte A β oligomers and destroy them by endolysosomal degradation, where microglial proteases such as neprilysin and insulin degrading enzyme (IDE) play an important role [91].”
BackgroundZhang, L., Xu, J., Gao, J., Chen, P., Yin, M., & Zhao, W. (2019) · Immunity & Ageing · doi:10.1186/s12979-018-0142-7 · Cited by 20
Song, C., Li, S., Mai, Y., Li, L., Dai, G., Zhou, Y., Liang, X., Zou, O. M., Wang, Y., Zhou, L., et al. (2024) · Journal of Neuroinflammation · doi:10.1186/s12974-024-03162-z · Cited by 19
“The Aβ peptides can also be up taken by phagocytosis of microglia and astrocytes, which also degrade Aβ by secreting a number of proteases [9].”
BackgroundCalpain-Mediated Alterations in Astrocytes Before and During Amyloid Chaos in Alzheimer’s Disease
Schultz, B., Taday, J., Menezes, L., Cigerce, A., Leite, M. C., & Gonçalves, C. (2021) · Journal of Alzheimer s Disease · doi:10.3233/jad-215182 · Cited by 19
Bocharova, O. V., Fisher, A., Pandit, N. P., Molesworth, K., Mychko, O., Scott, A. J., Makarava, N., Ritzel, R., & Baskakov, I. V. (2023) · Brain Pathology · doi:10.1111/bpa.13116 · Cited by 16
The Role of Astrocytes and Blood–Brain Barrier Disruption in Alzheimer’s Disease
Cruz, J. V. R., Batista, C., Diniz, L. P., & Mendes, F. A. (2023) · Neuroglia · doi:10.3390/neuroglia4030015 · Cited by 20
“In Alzheimer’s disease, the accumulation of tau in the astrocytes of the dentate gyrus leads to neuronal dysfunction and memory deficits [57].”
BackgroundEffect of memantine, an anti-Alzheimer’s drug, on rodent microglial cells in vitro
Murakawa‐Hirachi, T., Mizoguchi, Y., Ohgidani, M., Haraguchi, Y., & Monji, A. (2021) · Scientific Reports · doi:10.1038/s41598-021-85625-4 · Cited by 19
cGAS-STING signaling in Alzheimer's disease: Microglial mechanisms and therapeutic opportunities
Fazal, F., Dar, N. J., Ahamad, S., Khan, S., Bano, N., Saha, S., Nazir, A., & Bhat, S. A. (2026) · Molecular Aspects of Medicine · doi:10.1016/j.mam.2025.101444 · Cited by 21
Gong, Y., Li, Y., Liu, X., & He, L. (2021) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2021.174362 · Cited by 18
Zhou, X., Huang, K., Wang, Y., Zhang, Z., Liu, Y., Hou, Q., Yang, X., & Hoi, M. P. M. (2023) · Frontiers in Pharmacology · doi:10.3389/fphar.2023.1082602 · Cited by 18
“NEP degrades soluble Aβ monomers and oligomers while IDE only degrades soluble Aβ monomers (Jha et al., 2015; Ries & Sastre, 2016).”
BackgroundLi, J., Hao, Y., Wang, S., Li, W., Yue, S., Duan, X., Yang, Y., & Li, B. (2023) · Journal of Ethnopharmacology · doi:10.1016/j.jep.2023.117195 · Cited by 19
COVID‐19 and the impact on Alzheimer's disease pathology
Furman, S., Green, K. N., & Lane, T. E. (2023) · Journal of Neurochemistry · doi:10.1111/jnc.15985 · Cited by 18
“Both astrocytes and microglia have roles on A β clearance (Ries & Sastre, 2016) and APOE4 expression alters normal function of both of these cells.”
Yadav, V., Mythri, C., & Kumarasamy, M. (2024) · Brain Behavior and Immunity Integrative · doi:10.1016/j.bbii.2024.100048 · Cited by 22
Winham, C. L., Le, T., Jellison, E. R., Silver, A. C., Levesque, A. A., & Koob, A. O. (2019) · Neuroscience · doi:10.1016/j.neuroscience.2019.04.057 · Cited by 18
Late Passage Cultivation Induces Aged Astrocyte Phenotypes in Rat Primary Cultured Cells
Bang, M., Gonzales, E. L., Shin, C. Y., & Kwon, K. J. (2021) · Biomolecules & Therapeutics · doi:10.4062/biomolther.2020.175 · Cited by 19
“Astrocytes and microglia play an essential role in the phagocytosis of A through numerous receptors on the surface (Ries and Sastre, 2016).”
BackgroundInfluentialPrivitera, L., Hogg, E. L., Lopes, M., Domingos, L. B., Gaestel, M., Müller, J., Wall, M. J., & Corrêa, S. A. L. (2022) · Aging Cell · doi:10.1111/acel.13717 · Cited by 17
The Role of the Urea Cycle in the Alzheimer's Disease Brain
Al‐Thani, N. A., Stewart, G. S., & Costello, D. A. (2025) · Journal of Neurochemistry · doi:10.1111/jnc.70033 · Cited by 16
“…in glial cells and reactive astrocytes, as this system has been shown to mediate the activation of the urea cycle in primary astrocytes exposed to Aβ, with inhibition of ODC using DFMO downregulating autophagy-associated genes in this AD-astrocytic model (Ju et al. 2022; Ries and Sastre 2016).”
Lee, S., Ju, I. G., Choi, Y., Park, S., & Oh, M. G. (2021) · Toxins · doi:10.3390/toxins13120898 · Cited by 17
Otgongerel, D., Lee, H.-J., & Jo, S. A. (2022) · NeuroMolecular Medicine · doi:10.1007/s12017-022-08726-x · Cited by 17
“Aβs are removed mainly by Aβ-degrading enzymes (ADEs) such as neprilysin (NEP), insulin-degrading enzyme (IDE), and endothelinconverting enzyme1 (ECE1) (Ries & Sastre, 2016).”
BackgroundInfluentialSomin, S., Kulasiri, D., & Samarasinghe, S. (2023) · Translational Neurodegeneration · doi:10.1186/s40035-023-00344-2 · Cited by 18
“Many proteins play a crucial role in Aβ clearance, including apolipoprotein E (APOE) and α2-macroglobulin (α2-m) [82].”
BackgroundThe role of transient receptor potential (TRP) channels in phagocytosis: A comprehensive review
Alavi, M. S., Soheili, V., & Roohbakhsh, A. (2023) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2023.176302 · Cited by 18
Clark, A. T., Abrahamson, E. E., Harper, M. M., & Ikonomović, M. D. (2022) · Fluids and Barriers of the CNS · doi:10.1186/s12987-021-00301-z · Cited by 18
“In the aftermath of a brain injury, both pericytes and astrocytes are involved in reparatory processes [9, 21, 23] and are capable of clearing Aβ by an apolipoprotein E/low-density lipoprotein receptor-related protein 1 (LRP-1) mediated mechanism [6, 76, 82, 124, 126] and secretion of Aβ-degrading enzymes [108].”
BackgroundHuang, Y., Hsu, S.-M., Shie, F., Shiao, Y., Chao, L.-J., Chen, H., Yao, H.-H., Chien, M. A., Lin, C., & Tsay, H.-J. (2022) · PLoS ONE · doi:10.1371/journal.pone.0260966 · Cited by 17
“Second, astrocytes and microglia can degrade Aβ via internalization or releasing degradation enzymes [24].”
BackgroundMetkar, S. K., Girigoswami, A., BONDAGE, D. D., Shinde, U. G., & Girigoswami, K. (2022) · International Journal of Neuroscience · doi:10.1080/00207454.2022.2089137 · Cited by 17
Alzheimer's disease/dementia-associated brain pathology in aging DPP6-KO mice
Lin, L., Petralia, R. S., Holtzclaw, L. A., Wang, Y., Abebe, D. T., & Hoffman, D. A. (2022) · Neurobiology of Disease · doi:10.1016/j.nbd.2022.105887 · Cited by 17
“The substantial increases in size and number of astroglial and microglial processes that we describe here in the aging DPP6-KO mice are consistent with findings for AD/dementia, in which both astrocytes and microglia increase in activation and number and are attracted to accumulations of amyloid plaques and fibrils an…”
BackgroundResultFunctional antibody delivery: Advances in cellular manipulation
Koch, K. C., & Tew, G. N. (2022) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2022.114586 · Cited by 16
Key brain cell interactions and contributions to the pathogenesis of Alzheimer’s disease
Saavedra, J., Nascimento, M., Liz, M. A., & Cardoso, I. (2022) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2022.1036123 · Cited by 16
“The discovery of a link between neurodegeneration and vascular dysfunction pathways has resulted in new drug targets and therapeutic approaches for AD (Rius-Pérez et al., 2018).”
Background
Metadata
- Authors
- Ries, M., & Sastre, M.
- Affiliations
- Hammersmith Hospital (GB)
- Corresponding author
- Sastre, Magdalena
- Venue
- Frontiers in Aging Neuroscience
- Publisher
- Frontiers Media SA
- Published
- 2016-07-05
- Volume
- 8
- Pages
- 160-160
- ISSN
- 1663-4365 (ISSN-L)
- PMC
- PMC4932097
- OpenAlex
- W2460612985
- Cited by
- 527
- References
- 122
- Citations by year
- 2026: 32 · 2025: 53 · 2024: 62 · 2023: 60 · 2022: 77 · 2021: 76 · 2020: 57 · 2019: 47 · 2018: 32 · 2017: 31
- FWCI
- 4.31
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- Frontiers in Aging Neuroscience (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Spiral (Imperial College London) (submittedVersion, other-oa)
- Funders
- Medical Research Council
- 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 › Clinical Neurology › Cerebrospinal fluid and hydrocephalus
- Keywords
- amyloid-beta clearance, amyloid beta degradation, glial cells, microglia, astrocytes, Alzheimer's disease, neprilysin, insulin-degrading enzyme, endothelin-converting enzyme, matrix metalloproteinases, plasminogen activator, angiotensin-converting enzyme, extracellular chaperones, apolipoproteins, alpha2-macroglobulin, alpha-1-antichymotrypsin, phagocytosis
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