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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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Cites
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“Major challenges in Aβ-research comprise the complex peptide processing involving multiple proteases (6), the challenging physiochemical properties of the resulting fragments that permit a formation of different oligomeric structures (7), and the pleiotropic physiological effects of Aβpeptides on neurons, glia, and im…”
BackgroundThe implication of a diversity of non-neuronal cells in disorders affecting brain networks
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Alzheimer’s Disease and Premature Ovarian Insufficiency
Vujović, S., Ivović, M., Tančić‐Gajić, M., Marina, L., Jovičić-Pavlović, S., Pavlović, N., & Erić-Jovičić, M. (2023) · Endocrines · doi:10.3390/endocrines4020020 · Cited by 10
Effects of DHA (omega-3 fatty acid) and estradiol on amyloid β-peptide regulation in the brain
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Mechanistic Approach to Immunity and Immunotherapy of Alzheimer’s Disease: A Review
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“However, in the formerly analyzed models, mitochondrial alterations affected all cell-types, including those that likewise play crucial roles in amyloid elimination, like astrocytes [52, 53], pericytes [54–56], and endothelial cells [33, 54, 56].”
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Meox2 Haploinsufficiency Accelerates Axonal Degeneration in DBA/2J Glaucoma
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“The interaction among ACT, astrocytes, and Aβ plaques is believed to be involved in the pathogenesis of AD [13].”
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SARS-CoV-2-Induced Amyloidgenesis: Not One, but Three Hypotheses for Cerebral COVID-19 Outcomes
Gonçalves, C., Bobermin, L. D., Sesterheim, P., & Netto, C. A. (2022) · Metabolites · doi:10.3390/metabo12111099 · Cited by 10
“It is not our intention to discuss, in detail, the formation or clearance of Aβ or amyloid deposition (see [14,15] for a review).”
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Inhibition of insulin-degrading enzyme in human neurons promotes amyloid-β deposition
Rowland, H. A., Moxon, S. R., Corbett, N. J., Hanson, K., Fisher, K., Kellett, K. A. B., & Hooper, N. M. (2023) · Neuronal Signaling · doi:10.1042/ns20230016 · Cited by 15
“A limitation of our study is the use of neurons in isolation of other cell types present in the brain, particularly glia which are known to be involved in A β degradation and clearance [58].”
Connecting cellular mechanisms and extracellular vesicle cargo in traumatic brain injury
Ollen‐Bittle, N., Roseborough, A. D., Wang, W., Wu, J.-L. D., & Whitehead, S. N. (2023) · Neural Regeneration Research · doi:10.4103/1673-5374.391329 · Cited by 9
“Microglia are likely to be significant producers of Aβ-containing EVs post TBI as well given their known role in the clearance of Aβ (Ries and Sastre, 2016).”
BackgroundAbbott, V., Housden, B. E., & Houldsworth, A. (2025) · Brain Communications · doi:10.1093/braincomms/fcaf092 · Cited by 9
“123 Whilst astrocytes play an important role in maintaining a healthy CNS, the balance of reactive astrocytes is critical in preventing neuroin-flammation.”
Wang, Y., Wang, Z., Liu, Z., Li, J., Yang, S., Zhao, Y., Huang, Y., Liao, C., Zhang, Y., Zhao, J., et al. (2025) · Nature Communications · doi:10.1038/s41467-025-63458-3 · Cited by 13
“In the past decades, accumulated evidences indicated that anti-A β antibodies can bind to microglial FcR and/or Toll-like receptors 15 to activate microglia and increase their phagocytic ability 16,17 to clear A β plaques in the AD brain.”
Zhao, Z., Hood, R. J., Ong, L. K., Pietrogrande, G., Sanchez‐Bezanilla, S., Warren, K. E., Ilicic, M., Kluge, M. G., TeBay, C., Ottersen, O. P., et al. (2021) · Frontiers in Neurology · doi:10.3389/fneur.2021.585189 · Cited by 7
“The increase in RAGE may be best interpreted by considering the role of RAGE in facilitating microglial chemotaxis toward Aβ (59) and/or phagocytosis (60, 61).”
BackgroundHerrera, O. M. M., Hong, B. V., Mendiola, U. R., Maezawa, I., Jin, L., Lebrilla, C. B., Harvey, D. J., & Zivkovic, A. M. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms241210396 · Cited by 9
The Down-Expression of ACE and IDE Exacerbates Exogenous Amyloid-β Neurotoxicity in CB2R–/– Mice
Wang, L., Shi, F.-X., Xu, W., Cao, Y., Li, N., Li, M., Wang, Q., Wang, J., Tian, Q., Yu, L., et al. (2018) · Journal of Alzheimer s Disease · doi:10.3233/jad-180142 · Cited by 9
Patient-derived iPSCs, a reliable in vitro model for the investigation of Alzheimer’s disease
Asiamah, E. A., Guo, R., Kong, D., Feng, B., He, J., Zhang, W., Liu, X., Du, X., Ma, Z., Liu, B., et al. (2021) · Reviews in the Neurosciences · doi:10.1515/revneuro-2020-0065 · Cited by 9
Dual role of cofilin in APP trafficking and amyloid‐β clearance
Liu, T., Woo, J. A., Yan, Y., LePochat, P., Bukhari, M. Z., & Kang, D. E. (2019) · The FASEB Journal · doi:10.1096/fj.201901268r · Cited by 10
Wang, N., Jia, Y., Zhang, B., Li, Y., Murtaza, G., Huang, S.-M., & Liu, X. (2020) · Evidence-based Complementary and Alternative Medicine · doi:10.1155/2020/3862342 · Cited by 9
“NEP, a type II membrane-associated peptidase, is exclusively expressed in neurons and more evidence proved that NEP is the predominant ADE for degrading both monomeric and oligomeric forms of Aβ [15].”
BackgroundAmukti, D. P., Wazni, A. R., Irham, L. M., Sulistyani, N., Ma’ruf, M. F., Adikusuma, W., Sarasmita, M. A., Khairi, S., Purwanto, B. D., Suyatmi, S., et al. (2024) · E3S Web of Conferences · doi:10.1051/e3sconf/202450101021 · Cited by 8
Microbiota and Alzheimer’s disease: mechanistic insights from a multi-organ perspective
Liao, J., Mou, H., Luo, S., Shen, L., & Jiao, B. (2026) · Translational Neurodegeneration · doi:10.1186/s40035-026-00541-9 · Cited by 11
Hypochlorite-induced oxidation promotes aggregation and reduces toxicity of amyloid beta 1-42
Manucat-Tan, N. B., Chowdhury, A., Cataldi, R., Abdullah, R. Z., Kumita, J. R., & Wyatt, A. R. (2023) · Redox Biology · doi:10.1016/j.redox.2023.102736 · Cited by 8
“For example, activation of brain-resident immune cells is a fundamentally important defence mechanism that facilitates the clearance of neurotoxic Aβ from biological fluids [2].”
BackgroundRetractedLiu, L.-Z., Fan, S., Gao, J., Li, W., & Xian, X. (2023) · Brain Research Bulletin · doi:10.1016/j.brainresbull.2023.110683 · Cited by 9
Shaheen, H., Pal, S., & Melnik, R. (2023) · Physica D Nonlinear Phenomena · doi:10.1016/j.physd.2023.133839 · Cited by 8
Recent advances in Alzheimer’s disease pathogenesis and therapeutics from an immune perspective
Nguyen, T.-D., Dang, L. N., Jang, J., & Park, S. (2023) · Journal of Pharmaceutical Investigation · doi:10.1007/s40005-023-00631-0 · Cited by 9
Hong, X., Chen, T., Liu, Y., Li, J., Huang, D., Ye, K., Liao, W., Wang, Y., Liu, M., & Luan, P. (2025) · Ageing Research Reviews · doi:10.1016/j.arr.2025.102669 · Cited by 9
Choi, J., Kwon, H., & Han, P. (2021) · Experimental Neurobiology · doi:10.5607/en21014 · Cited by 8
“Beta-amyloid clearance can be regulated by β-amyloid degrading enzymes, including insulindegrading enzyme (IDE), neprilysin (NEP), matrix metalloproteinases 2 and 9 (MMP-2/9), and tissue/urokinase plasminogen activators (tPA/uPA) [27].”
BackgroundAsiamah, E. A., Feng, B., Guo, R., Yaxing, X., Du, X., Liu, X., Zhang, J., Cui, H., & Ma, J. (2024) · Journal of Alzheimer s Disease · doi:10.3233/jad-230658 · Cited by 8
“:3) across the blood-brain barrier (BBB) [64].”
Chiarini, A., Armato, U., Gui, L., Yin, M., Chang, S., & Prà, I. D. (2024) · Brain Research · doi:10.1016/j.brainres.2024.149283 · Cited by 7
“From a theoretical standpoint, A β⋅ Rs complexes might trigger either harmful or protective responses (Ries and Sastre, 2016).”
BackgroundAsadie, M., Miri, A., Badri, T., Nejad, J. H., & Gharechahi, J. (2024) · Journal of Molecular Neuroscience · doi:10.1007/s12031-024-02212-8 · Cited by 7
“Angiogenesis mostly assumed a pathogenic character, leading to the leaking of blood components and the aggravation of the neuroinflammatory state (Ries and Sastre 2016).”
The role of the gut microbiome in the regulation of astrocytes in Alzheimer's disease
Chandra, S., & Vassar, R. J. (2024) · Neurotherapeutics · doi:10.1016/j.neurot.2024.e00425 · Cited by 7
Ramachandran, A. K., Das, S., Shenoy, G. G., Mudgal, J., & Joseph, A. (2022) · CNS & Neurological Disorders - Drug Targets · doi:10.2174/1871527322666221226145141 · Cited by 7
Ion transporter cascade, reactive astrogliosis and cerebrovascular diseases
Rahman, M. S., Islam, R., & Bhuiyan, M. I. H. (2024) · Frontiers in Pharmacology · doi:10.3389/fphar.2024.1374408 · Cited by 8
“Microglia and astrocytes clear pathological A β deposits through phagocytosis and degrades in CNS and moderately improves spatial working memory (Ries and Sastre, 2016; Sevigny et al., 2016; Kong et al., 2022).”
BackgroundMisfolded proteins as a therapeutic target in Alzheimer's disease
Liyanage, S. I., & Weaver, D. F. (2019) · Advances in protein chemistry and structural biology · doi:10.1016/bs.apcsb.2019.08.003 · Cited by 8
Role of neprilysin in synaptic plasticity and memory
Nalivaeva, N. N., Vasilev, D. S., Dubrovskaya, N. M., Turner, A. J., & Zhuravin, I. A. (2020) · Российский физиологический журнал им И М Сеченова · doi:10.31857/s0869813920100076 · Cited by 7
Glial Regulation of Circuit Wiring, Firing, and Expiring in theDrosophilaCentral Nervous SystemPreprint
Coutinho‐Budd, J., Freeman, M. R., & Ackerman, S. D. (2024) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a041347 · Cited by 8
Tada, A. M., Hamezah, H. S., Arrozi, A. P., Bakar, Z. H. A., Yanagisawa, D., & Tooyama, I. (2022) · Journal of Alzheimer's Disease · doi:10.3233/jad-220192 · Cited by 4
Du, X., Wang, H., Liu, S., Song, Y., Chen, X., Chen, Z., Zhou, R., Du, J., Zhang, W., Gao, R., et al. (2025) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2025.102744 · Cited by 6
Astrocyte response in Alzheimer’s disease: Good or bad?
Ismail, A., Al-Kuraishy, H. M., Al-Gareeb, A. I., Albuhadily, A. K., Yassen, A. S. A., Alexiou, A. T., Papadakis, M., & Batiha, G. E. (2025) · Brain Research · doi:10.1016/j.brainres.2025.149971 · Cited by 6
Cholesterol metabolism regulates Tauopathy in Alzheimer’s disease
Chinnathambi, S., Adityan, A., & Chandrashekar, M. (2024) · Advances in protein chemistry and structural biology · doi:10.1016/bs.apcsb.2024.11.005 · Cited by 6
West Nile virus non-structural protein 1 promotes amyloid Beta deposition and neurodegeneration
Beltrami, S., Rizzo, S., Schiuma, G., Cianci, G., Narducci, M., Baroni, M., Luca, D. D., Rizzo, R., & Bortolotti, D. (2025) · International Journal of Biological Macromolecules · doi:10.1016/j.ijbiomac.2025.141032 · Cited by 10
da Luz, M. H. M., Pino, J. M. V., Mônico‐Neto, M., Nicolicht, P., Antunes, H. K. M., Porcionatto, M. A., & Lee, K. S. (2023) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2023.166729 · Cited by 6
Cellular prion protein offers neuroprotection in astrocytes submitted to amyloid β oligomer toxicity
Marques, C. M. S., Gomes, R. N., Pedron, T., Batista, B. L., & Cerchiaro, G. (2022) · Molecular and Cellular Biochemistry · doi:10.1007/s11010-022-04631-w · Cited by 6
“Astrocytes could internalize and degrade toxic β-amyloid peptides as a crucial defense role in developing and advancing AD [43, 101, 102].”
BackgroundPark, S.-H., Lee, J.-Y., Jhee, K.-H., & Yang, S.-A. (2020) · Toxicology Reports · doi:10.1016/j.toxrep.2020.08.032 · Cited by 6
Sirimaharaj, N., Thiankhaw, K., Chattipakorn, N., & Chattipakorn, S. C. (2025) · Molecular Neurobiology · doi:10.1007/s12035-025-04904-7 · Cited by 5
“For instance, treatments aimed at reducing inflammation could help modulate the mixed inflammatory response caused by tau, whereas antioxidant therapies might be more effective in combating the oxidative stress induced by Aβ [39].”
InfluentialWood, J. I., Dulewicz, M., Szadziewska, A., Weiner, S., Ge, J., Stringer, K. M., Desai, S., Fenson, L., Piotrowska, D., Brinkmalm, G., et al. (2025) · Nature Communications · doi:10.1038/s41467-025-63328-y · Cited by 14
Böswald, L. F., Wenderlein, J., Bachmann, M., Zeyner, A., Neuhaus, K., Schäfer, F., Imhof, A., Lahiri, S., Grützke, J., & Popper, B. (2025) · Scientific Reports · doi:10.1038/s41598-025-20986-8 · Cited by 7
“As microglia play a pivotal role in avoiding amyloid plaque formation by both active plaque clearance and by stimulating neurons towards non-amyloidogenic pathway of APP processing 123–125 , this matches our observation of reduced Aβ load as well.”
Network Models of Neurodegeneration: Bridging Neuronal Dynamics and Disease Progression
Alexandersen, C. G., Brennan, G. S., Brynildsen, J. K., Henderson, M. X., Iturria‐Medina, Y., & Bassett, D. S. (2026) · IEEE Reviews in Biomedical Engineering · doi:10.1109/rbme.2025.3643310 · Cited by 9
“Microglia, the brain’s resident immune cells, facilitate clearance of amyloid and tau through proteases and chaperones [153].”
Singh, A. S., Naqvi, A. R., & Chanu, M. T. (2026) · Journal of Psychiatric Research · doi:10.1016/j.jpsychires.2026.01.050 · Cited by 7
Webster, J. M., Yang, Y.-T., Miller, A. T., Zane, A., Scholz, K., Stone, W. J., Mudium, N., Corbin-Stein, N. J., Won, W.-J., Stoll, A. C., et al. (2026) · Neurobiology of Disease · doi:10.1016/j.nbd.2026.107323 · Cited by 13
Diabetes mellitus and Alzheimer's disease: Vacuolar adenosine triphosphatase as a potential link
Guo, B., Li, Q., Liu, X. M., Luo, G., Wu, Y., & Nie, J. (2024) · European Journal of Neuroscience · doi:10.1111/ejn.16286 · Cited by 5
“Various types of brain cells are involved in the regulation of A β levels in the brain (Nalivaeva et al., 2012; Ries & Sastre, 2016).”
BackgroundThe identification of a Distinct Astrocyte Subtype that Diminishes in Alzheimer’s Disease
Wei, H., Withrow, J. S., Rakshit, J., Amin, F. U., Nahm, J., Mowry, F. E., Mao, Z., Bhattacharjee, M. B., Zhu, J., Yang, Y., et al. (2024) · Aging and Disease · doi:10.14336/ad.2024.0205-1 · Cited by 7
“However, astrocytes also have protective functions and can help clear amyloid beta and internalize tau from the brain [12-17].”
Anastacio, H. T. D., Matosin, N., & Ooi, L. (2024) · Life · doi:10.3390/life14050625 · Cited by 6
“Apart from the different types of controls used, the presence of glial cells in the culture can also affect the A β phenotype, as they are involved in the clearance of this peptide [57].”
BackgroundZhang, Y., Wang, J., Zhang, H., Tan, Z., Zheng, Y., Ping, J., Zhang, J., Luo, J., Li, L., Lu, L., et al. (2024) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2024.1461556 · Cited by 5
“Furthermore, research indicates that activated astrocytes are involved in the degradation or clearance of A β , hinting at their potential as a novel therapeutic target in AD (Ries and Sastre, 2016).”
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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