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]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
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]
In the citing paper
“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
Amyloid oligomers exacerbate tau pathology in a mouse model of tauopathy
Selenica, M.-L. B., Brownlow, M., Jimenez, J. P., Lee, D. C., Pena, G., Dickey, C. A., Gordon, M. N., & Morgan, D. (2013) · Neurodegenerative Diseases · doi:10.1159/000337230 · Cited by 10,359
Harold, D., Abraham, R., Hollingworth, P., Sims, R., Gerrish, A., Hamshere, M. L., Pahwa, J. S., Moskvina, V., Dowzell, K., Williams, A., et al. (2009) · Nature Genetics · doi:10.1038/ng.440 · Cited by 3,326 · cited 1×
“…160 ApoE mutations (Verghese et al., 2013) Metal ions affect expression of IDE, NEP and metalloproteases (Sastre et al., 2015) ApoJ mutations (Harold et al., 2009) Insulin/diabetes affects IDE levels (Steneberg et al., 2013) Presenilin mutations affect microglia function (Farfara et al.,…”
Cellular Scaling Rules for the Brains of Marsupials: Not as “Primitive” as Expected
Santos, S. E. D., Porfírio, J., Cunha, F., Manger, P. R., Tavares, W. C., Pessôa, L. M., Raghanti, M. A., Sherwood, C. C., & Herculano‐Houzel, S. (2017) · Brain Behavior and Evolution · doi:10.1159/000452856 · Cited by 2,652
Role of Oxidative Modifications in Atherosclerosis
Stocker, R., & Keaney, J. F. (2004) · Physiological Reviews · doi:10.1152/physrev.00047.2003 · Cited by 2,651 · cited 9×
“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.”
BackgroundInfluentialRock, K. L., Gramm, C., Rothstein, L., Clark, K., Stein, R., Dick, L., Hwang, D., & Goldberg, A. L. (1994) · Cell · doi:10.1016/s0092-8674(94)90462-6 · Cited by 2,524 · cited 2×
“The ubiquitin proteasome system (UPS) is a mechanism of protein degradation which selectively targets individual proteins, including short-lived, damaged, or defectively folded proteins (Rock et al., 1994; Lilienbaum, 2013).”
BackgroundThe NALP3 inflammasome is involved in the innate immune response to amyloid-β
Halle, A., Hornung, V., Petzold, G. C., Stewart, C. R., Monks, B. G., Reinheckel, T., Fitzgerald, K. A., Latz, E., Moore, K. J., & Golenbock, D. T. (2008) · Nature Immunology · doi:10.1038/ni.1636 · Cited by 2,441 · cited 1×
“It has been described that after being phagocytosed by microglia, Aβ can be degraded by cathepsin B (CAT-B) (Nakanishi, 2003; Halle et al., 2008).”
BackgroundAzevedo, F. A. C., Carvalho, L. R. B., Grinberg, L. T., Farfel, J. M., Ferretti, R. E. L., Leite, R. E. P., Filho, W. J., Lent, R., & Herculano‐Houzel, S. (2009) · Journal of Comparative Neurology · doi:10.1002/cne.21974 · Cited by 2,337 · cited 1×
“Glial cells represent around 50% of the cells in the human brain (Azevedo et al., 2009).”
BackgroundDifferential Roles of M1 and M2 Microglia in Neurodegenerative Diseases
Tang, Y., & Le, W. (2016) · Molecular Neurobiology · doi:10.1007/s12035-014-9070-5 · Cited by 2,190 · cited 1×
“This function seems to be associated with a special and particular phenotype in microglia (formally known as M2 or alternatively activated) in contrast with the pro-inflammatory M1 state (Tang and Le, 2016).”
BackgroundBard, F., Cannon, C., Barbour, R., Burke, R.-L., Games, D., Grajeda, H., Guido, T., Hu, K., Huang, J., Johnson-Wood, K., et al. (2000) · Nature Medicine · doi:10.1038/78682 · Cited by 2,012 · cited 1×
“The FcRs have been shown to mediate Aβ clearance in the presence of anti-Aβ antibodies (Bard et al., 2000; Wilcock et al., 2003), as observed in Aβ immunization therapies (Bacskai et al., 2002).”
BackgroundTREM2 Lipid Sensing Sustains the Microglial Response in an Alzheimer’s Disease Model
Wang, Y., Cella, M., Mallinson, K., Ulrich, J. D., Young, K. L., Robinette, M. L., Gilfillan, S., Krishnan, G. M., Sudhakar, S., Zinselmeyer, B. H., et al. (2015) · Cell · doi:10.1016/j.cell.2015.01.049 · Cited by 1,736
Flagged first, then by citations
3 of the 122 references couldn’t be matched to a known paper.
Research works printed but not linked: 2
- Lilienbaum, 2013, Relationship between the proteasomal system, and autophagy., Int. J. Biochem. Mol. Biol., 4, 1
- Love, 2004, Contribution of cerebral amyloid angiopathy to Alzheimer’s disease., J. Neurol. Neurosurg. Psychiatry, 75, 1
Cited by
Sorted by citations
Items 501–533 of 533
Vautheny, A. (2019) · theses.fr (ABES) · doi:10.70675/1812d71aze8d9z48d6z87d1z5a23a4e81953
Implication du fragment C99 dans l’avènement des phénotypes pathologiques de la maladie d’Alzheimer
Bourgeois, A. (2019) · theses.fr (ABES) · doi:10.70675/bb8ccf34zec6cz4bb6z82b4z3030b9cb28f7
Abdelouahab, O. B. (2021) · theses.fr (ABES) · doi:10.70675/97f4885fz3f5cz4234zb8e2ze3fa7c4e3d41
Hétérogénéité de la réactivité astrocytaire dans la maladie d'Alzheimer
Guillemaud, O. (2020) · theses.fr (ABES) · doi:10.70675/038d98c5z55ccz4754z9af9z417e3826d282
Lam, S. (2021) · theses.fr (ABES) · doi:10.70675/60b353ffz56fcz41a2z9e53zf0d9ac078167 · Cited by 1
Poulot-Becq-Giraudon, Y. (2024) · theses.fr (ABES) · doi:10.70675/0d7a8b92z8393z4d76z82a8z87efe0790346
Rafiee, Z., Santiago, J., Andersson, E., Hansson, O., & Wennström, M. (2026) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2026.1766448
Exploring peripheral immune mechanisms and potential therapeutic drugs for Alzheimer’s disease
Zhu, W., Zhou, D., Zhang, G., & Dai, W. (2026) · Naunyn-Schmiedeberg s Archives of Pharmacology · doi:10.1007/s00210-026-05397-4
Visceral adipose tissue differentially affects tau and Aβ pathology in 3xTg-AD mice
Trujillo‐Estrada, L., Bettinetti‐Luque, M., Andreo‐Lopez, J., Cunha, C. D., Morales‐Cabello, M., Campos‐Moreno, C., Sánchez‐Mejías, E., Forner, S., Martini, A. C., Sanchez-Varo, R. M., et al. (2026) · Cell Communication and Signaling · doi:10.1186/s12964-026-02964-3
“Additionally, we evaluated the effects of fat transplantation on the major Aβ-degrading enzymes [66, 67], such as neprilysin and insulin degrading enzyme (IDE), and found no differences between groups.”
Day, S. M., Reitz, N. L., & Savage, L. M. (2026) · Journal of Alzheimer s Disease · doi:10.1177/13872877261453081 · Cited by 1
Glial cells in neurodegenerative diseases: a review
Pranto, A. H., Khandker, S. S., Uddin, M. E., Aktar, S., Mumu, S. I., Khan, R. I., Chowdhury, N. K., Prekbunjun, J., Zisan, A., & Begum, R. (2025) · Neurophysiology · doi:10.1007/s11062-026-10018-0
“In AD, astrocytes contribute to the clearance of Amyloid-β (A β ) via processes like enzymatic degradation and phagocytosis [31].”
InfluentialThe Dual Roles of Extracellular Vesicle Subtypes in Regulating Traumatic Brain Injury
Zhang, X., Zhou, C., & Xu, Y. (2026) · International Journal of Molecular Sciences · doi:10.3390/ijms27125322
Dey, A., Sanyal, D., Chattopadhyay, K., Maulik, U., Uversky, V. N., & Sen, S. (2026) · International Journal of Molecular Sciences · doi:10.3390/ijms27125627
Mutant huntingtin in the extracellular matrix: A new perspective on Huntington's disease pathology
Trabolsi, C., & Cicchetti, F. (2026) · Neurobiology of Disease · doi:10.1016/j.nbd.2026.107502
Seo, G., Hwang, S., Kim, B.-Y., Lee, J. Y., Yoon, Y. D., & Baek, S. (2026) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2026.579024
Apostol, A., Kuzubova, E. V., Radchenko, A. I., Chaprov, K., Щеблыкина, О. В., Романович, Л. П., Korokina, L. V., Pokrovskii, M., Sedinova, V. N., Khizeva, A., et al. (2026) · Biomedicines · doi:10.3390/biomedicines14071524
Shrinking of Extracellular Space During Metabolic Stress Accelerates Amyloid-β Aggregation
Oliveira, L. F. D., Karunarathne, K., Zona, D., Muschol, M., & Ullah, G. (2026) · Biomolecules · doi:10.3390/biom16071053
The human retina in Alzheimer’s disease: Pathology, mechanisms, and biomarkers
Müller, L. P. D. S., Majumdar, S., & Recio, B. S. (2026) · Ageing Research Reviews · doi:10.1016/j.arr.2026.103275
Calvano, A., & van Wamelen, D. J. (2026) · International review of neurobiology · doi:10.1016/bs.irn.2026.08.017
Aggregated amyloid-β(1-42) is internalized more efficiently than monomers by HEK293T cells
Pereira, C. S., Abid, H., Adair, C., Domalewski, R. J., Jabr, L., & Nichols, M. R. (2026) · Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics · doi:10.1016/j.bbapap.2026.141178
Seol, S.-I., Kim, J., Davaanyam, D., Park, S., Lee, E.-H., Han, P.-L., Kim, T.-K., & Lee, J.-K. (2026) · International Journal of Molecular Sciences · doi:10.3390/ijms27198681
“Neurons express and utilize NEP, IDE, MMP2/9, and tPA, while microglia primarily rely on IDE and MMP9 to clear extracellular A β [66,80,81].”
Lv, C., Luo, Q., Jin, F., Shao, Q., Qiu, Y., Junjun, N., Liu, J., Qing, H., & Quan, Z. (2026) · Journal of Alzheimer s Disease · doi:10.1177/13872877261497235
Roy, J., Tsui, K. C., Poon, C. H., Zhang, J., Lai, Y., Wong, K. Y., Mihardja, M., Tse, V., Li, P. C., Au, C., et al. (2026) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2026.107077
Jacquier‐Sarlin, M. R., Seignobos, M., Rauzier, L., Schaack, B., Laurin, D., & Buisson, A. (2026) · Frontiers in Neuroscience · doi:10.3389/fnins.2026.1963040
“…and autophagy lysosomal systems (Wang et al., 2025), whereas extracellular A β is eliminated through microglial and astrocytic phagocytosis (Ries and Sastre, 2016), enzymatic degradation by neprilysin and insulin-degrading enzyme (Yasojima et al., 2001; Farris et al., 2003), glymphatic…”
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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