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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]
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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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“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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Sorted by citations
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BackgroundMetformin treatment prevents amyloid plaque deposition and memory impairment in APP/PS1 mice
Ou, Z., Kong, X., Sun, X., He, X., Zhang, L., Gong, Z., Huang, J., Xu, B., Long, D., Li, J., et al. (2017) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2017.12.009 · Cited by 372
“Conversely, activation of these cells is important for the clearance of Aβ plaques through induction of phagocytosis (Ries and Sastre, 2016), demonstrating a dual role for neuroinflammation on Aβ pathology.”
The Pivotal Role of NF-kB in the Pathogenesis and Therapeutics of Alzheimer’s Disease
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“Astrocytes however more likely participate in Aβ clearance, not in Aβ production, by secreting apolipoprotein E (ApoE), apolipoprotein J (ApoJ), α1-antichymotrypsin (ACT) and α2macroglobulin (α2-M) that promote Aβ transport over the BBB via low-densitylipoprotein-receptor-related-protein-1 (LRP1) and very-low-density-…”
Astrocyte Biomarkers in Alzheimer’s Disease
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PSEN1 Mutant iPSC-Derived Model Reveals Severe Astrocyte Pathology in Alzheimer's Disease
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“Astrocytes are thought to play a critical role in Ab clearance (Ries and Sastre, 2016), while neurons have generally been considered as themain Ab producers (Zhao et al., 1996).”
BackgroundMicroglia-Mediated Synapse Loss in Alzheimer's Disease
Rajendran, L., & Paolicelli, R. C. (2018) · The Journal of Neuroscience · doi:10.1523/jneurosci.1136-17.2017 · Cited by 355
“In the case of microglial removal of amyloid, phagocytosis is one of the well-studied mechanisms (Ries and Sastre, 2016).”
BackgroundPhagocytosis in the Brain: Homeostasis and Disease
Galloway, D. A., Phillips, A. E. M., Owen, D. R., & Moore, C. S. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.00790 · Cited by 319
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Onyango, I. G., Jauregui, G. V., Čarná, M., Bennett, J. P., & Stokin, G. B. (2021) · Biomedicines · doi:10.3390/biomedicines9050524 · Cited by 330
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“Microglial phagocytosis of Aβ is essential for clearing Aβ deposits and is considered a neuroprotective mechanism (Ries and Sastre, 2016).”
BackgroundMicroglia and the aging brain: are senescent microglia the key to neurodegeneration?
Angelova, D. M., & Brown, D. R. (2019) · Journal of Neurochemistry · doi:10.1111/jnc.14860 · Cited by 262
“Therefore, one of the functions of microglia is degradation of b-amyloid (Ries and Sastre 2016).”
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Fernandez, C. G., Hamby, M. E., McReynolds, M. L., & Ray, W. J. (2019) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2019.00014 · Cited by 277
“APOE Isoforms and Amyloid Clearance Both astrocytes and microglia clear Aβ (Paresce et al., 1996; Wyss-Coray et al., 2003; Ries and Sastre, 2016) and although there is some evidence that APOE4 may enhance Aβ production (Ye et al.”
BackgroundSimon, M. J., Wang, M. X., Ismail, O., Braun, M., Schindler, A. G., Reemmer, J., Wang, Z., Haveliwala, M. A., O’Boyle, R. P., Han, W., et al. (2022) · Alzheimer s Research & Therapy · doi:10.1186/s13195-022-00999-5 · Cited by 293
Innate Immune Cell Death in Neuroinflammation and Alzheimer’s Disease
Rajesh, Y., & Kanneganti, T. (2022) · Cells · doi:10.3390/cells11121885 · Cited by 269
Urolithin A attenuates memory impairment and neuroinflammation in APP/PS1 mice
Gong, Z., Huang, J., Xu, B., Ou, Z., Zhang, L., Lin, X., Ye, X., Kong, X., Long, D., Sun, X., et al. (2019) · Journal of Neuroinflammation · doi:10.1186/s12974-019-1450-3 · Cited by 265
“Conversely, activated glia also promoted the phagocytosis of the Aβ oligomer [5].”
TDP-43 depletion in microglia promotes amyloid clearance but also induces synapse loss
Paolicelli, R. C., Jawaid, A., Henstridge, C. M., Valeri, A., Merlini, M., Robinson, J. L., Lee, E. B., Rose, J., Appel, S., Lee, V. M.-Y., et al. (2017) · Neuron · doi:10.1016/j.neuron.2017.05.037 · Cited by 239
“(legend continued on next page) 298 Neuron 95, 297–308, July 19, 2017 intracellularly through enzymatic degradation following phagocytosis or extracellularly through degradation by secreted enzymes (Vekrellis et al., 2000; Nakanishi, 2003; Ries and Sastre, 2016; Solé-Domènech et al., 2016).”
BackgroundTargeting Neuroinflammation to Treat Alzheimer’s Disease
Ardura-Fabregat, A., Boddeke, E., Boza‐Serrano, A., Brioschi, S., Castro‐Gomez, S., Ceyzériat, K., Dansokho, C., Dierkes, T., Gelders, G., Heneka, M. T., et al. (2017) · CNS Drugs · doi:10.1007/s40263-017-0483-3 · Cited by 241
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Cholesterol and Alzheimer’s Disease; From Risk Genes to Pathological Effects
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“Both astrocytes and microglia can phagocytose Aβ, thereby contributing to Aβ clearance from the brain (TarasoffConway et al., 2015; Ries and Sastre, 2016).”
BackgroundCellular and pathological heterogeneity of primary tauopathies
Chung, D. C., Roemer, S. F., Petrucelli, L., & Dickson, D. W. (2021) · Molecular Neurodegeneration · doi:10.1186/s13024-021-00476-x · Cited by 232
“In vitro studies show astrocytes can mediate Aβ clearance by phagocytosis [117], and several studies have similarly demonstrated that astrocytes can also take up and degrade pathological tau species from the extracellular space [118, 119].”
BackgroundOld Maids: Aging and Its Impact on Microglia Function
Koellhoffer, E. C., McCullough, L. D., & Ritzel, R. M. (2017) · International Journal of Molecular Sciences · doi:10.3390/ijms18040769 · Cited by 213
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“Peptidases such as neprilysin (NEP), insulin-degrading enzyme (IDE), endothelin-converting enzyme (ECE), and matrix metalloproteinases (MMPs) are expressed in astrocytes, and are involved in the degradation of extracellular forms of Aβ [104,105].”
BackgroundThe duality of amyloid-β: its role in normal and Alzheimer’s disease states
Azargoonjahromi, A. (2024) · Molecular Brain · doi:10.1186/s13041-024-01118-1 · Cited by 214
“However, in AD, the expression and activity of these enzymes are often reduced, leading to less efficient degradation of Aβ and its subsequent accumulation in the extracellular space [229, 230].”
BackgroundNew mechanism of nerve injury in Alzheimer’s disease: β‐amyloid‐induced neuronal pyroptosis
Han, C., Yang, Y., Guan, Q., Zhang, X., Shen, H., Sheng, Y., Wang, J., Zhou, X., Li, W., Guo, L., et al. (2020) · Journal of Cellular and Molecular Medicine · doi:10.1111/jcmm.15439 · Cited by 193
Astrocyte Senescence and Alzheimer’s Disease: A Review
Han, X., Zhang, T., Liu, H., Mi, Y., & Gou, X. (2020) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2020.00148 · Cited by 177
“Astrocyte receptors involved in uptake and clearance of Aβ are the low-density lipoprotein receptor-related protein 1 (LRP1) and scavenger receptor B1 (SR-B1) (Basak et al., 2012; Ries and Sastre, 2016).”
BackgroundAstrocytes in Alzheimer's disease: pathological significance and molecular pathways
Preman, P., Alfonso-Triguero, M., Alberdi, E., Verkhratsky, A., & Arranz, A. M. (2021) · Cells · doi:10.3390/cells10030540 · Cited by 176
Targeting amyloid clearance in Alzheimer's disease as a therapeutic strategy
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“Furthermore, astrocytes express several proteases and receptors involved in the biogenesis of A , which includes neprilysin, insulin-degrading enzyme and endothelin-converting enzyme 1/2, being involved in the degradation and clearance of the peptide [128, 129].”
BackgroundMolecular Mechanisms of Neuroinflammation in Aging and Alzheimer’s Disease Progression
Andronie-Cioară, F. L., Ardelean, A. I., Nistor-Cseppento, C. D., Jurcău, A., Jurcău, M. C., Pașcalău, N., & Marcu, F. M. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24031869 · Cited by 170
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Glia Crosstalk in Neuroinflammatory Diseases
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“However, when the clearance is not sufficient, the proinflammatory profile chronifies, and then both microglia and astrocyte acquire a new deleterious profile (for review see Ries and Sastre, 2016).”
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Astrocytic urea cycle detoxifies Aβ-derived ammonia while impairing memory in Alzheimer’s disease
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The Emerging Role of Central and Peripheral Immune Systems in Neurodegenerative Diseases
Zang, X., Chen, S., Zhu, J., Ma, J., & Zhai, Y. (2022) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2022.872134 · Cited by 139
“Activated microglia have the capacity to remove excess Aβ plaques and cellular debris (Ries and Sastre, 2016).”
BackgroundWang, Z., Zhao, Y., Xu, N., Zhang, S., Wang, S., Mao, Y., Zhu, Y., Li, B. J., Jiang, Y., Tan, Y. C., et al. (2019) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-019-03074-9 · Cited by 137
“The internalization of oligomeric or fibrillary Aβ requires a number of receptors for endocytosis [48].”
BackgroundRangaraju, S., Dammer, E. B., Raza, S. A., Gao, T., Xiao, H., Betarbet, R. S., Duong, D. M., Webster, J. A., Hales, C. M., Lah, J. J., et al. (2018) · Molecular Neurodegeneration · doi:10.1186/s13024-018-0266-4 · Cited by 138
“Since activated microglia engulf Aβ and Apoe strongly co-localizes with Aβ within microglia, our findings suggest that microglia may either phagocytose Aβ and Apoe that co-aggregate in the AD brain or that Apoe’s co-localization with Aβ indicates functional interaction between Aβ and Apoe during Aβ phagocytosis and cl…”
BackgroundLoss of canonical Wnt signaling is involved in the pathogenesis of Alzheimer’s disease.
Inestrosa, N., & Tapia-Rojas, C. (2018) · Neural Regeneration Research · doi:10.4103/1673-5374.238606 · Cited by 137
“Among these mechanisms, TREM2 (an innate immune receptor and a Type I transmembrane protein) regulates phagocytosis and promotes microglial survival, contributing to Aβ elimination (Ries and Sastre, 2016).”
Astrocyte metabolism and signaling pathways in the CNS
Zhang, Y.-M., Qi, Y., Gao, Y.-N., Chen, W.-G., Zhou, T., Zang, Y., & Li, J. X. (2023) · Frontiers in Neuroscience · doi:10.3389/fnins.2023.1217451 · Cited by 152
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Tao, L., Liu, Q., Zhang, F., Fu, Y., Zhu, X. D., Weng, X., Han, H., Huang, Y., Suo, Y., Chen, L., et al. (2021) · Light Science & Applications · doi:10.1038/s41377-021-00617-3 · Cited by 133
Glymphatic system disruption as a mediator of brain trauma and chronic traumatic encephalopathy
Sullan, M. J., Asken, B. M., Jaffee, M. S., DeKosky, S. T., & Bauer, R. M. (2017) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2017.08.016 · Cited by 135
“However, the current CTE literature provides evidence for the role of GS dysfunction due to the overlap between the neural structures commonly associated with CTE pathology and those involved in the GS.”
InfluentialBlood-brain barrier integrity in the pathogenesis of Alzheimer’s disease
Huang, Z., Wong, L., Su, Y., Huang, X., Wang, N., Chen, H., & Yi, C. (2020) · Frontiers in Neuroendocrinology · doi:10.1016/j.yfrne.2020.100857 · Cited by 135
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“(1,10,11), the main component of the amyloid plaques found in Alzheimer’s disease brain.”
BackgroundKoelsch, G. (2017) · Molecules · doi:10.3390/molecules22101723 · Cited by 128
“Extant Aβ is not reduced by BACE1 inhibition, and therefore reduction of Aβ is achieved by innate clearance mechanisms, including phagocytosis [156], transport proteins [156,157], and a growing list of candidate proteases that act upon soluble and insoluble forms of amyloid [158].”
BackgroundCano, A., Turowski, P., Ettcheto, M., Duskey, J. T., Tosi, G., Sánchez-López, E., García, M. L., Camins, A., Souto, E. B., Ruiz, A., et al. (2021) · Journal of Nanobiotechnology · doi:10.1186/s12951-021-00864-x · Cited by 122
“Since the dysregulation of clearance mechanisms has been identified as a direct cause of AD development, proteins related to the removal of cerebral metabolic waste, Aβ and p-tau peptides, and reactive oxidative species have been suggested as candidate biomarkers [27, 98].”
BackgroundNLRP3 inflammasome signalling in Alzheimer's disease
McManus, R. M., & Latz, E. (2024) · Neuropharmacology · doi:10.1016/j.neuropharm.2024.109941 · Cited by 136
“A β and tau are first phagocytosed by TLR2, TLR4 and other scavenger receptors (Sheedy et al., 2013; Ries and Sastre, 2016; Meng et al., 2022; McManus, 2022).”
BackgroundThe role of innate immunity in Alzheimer's disease
Ennerfelt, H. E., & Lukens, J. R. (2020) · Immunological Reviews · doi:10.1111/imr.12896 · Cited by 124
Noncanonical function of an autophagy protein prevents spontaneous Alzheimer’s disease
Heckmann, B. L., Teubner, B. J. W., Boada-Romero, E., Tummers, B., Guy, C., Fitzgerald, P., Mayer, U., Carding, S., Zakharenko, S. S., Wileman, T., et al. (2020) · Science Advances · doi:10.1126/sciadv.abb9036 · Cited by 114
Ultrastructural evidence of microglial heterogeneity in Alzheimer’s disease amyloid pathology
El Hajj, H., Savage, J. C., Bisht, K., Parent, M., Vallières, L., Rivest, S., & Tremblay, M.-È. (2019) · Journal of Neuroinflammation · doi:10.1186/s12974-019-1473-9 · Cited by 119
Neuroinflammation in mouse models of Alzheimer's disease
Saito, T., & Saido, T. C. (2018) · Clinical and Experimental Neuroimmunology · doi:10.1111/cen3.12475 · Cited by 118
“Although the primary function of the plaque-associated astrocytic response remains unclear, deletion of the glial filament proteins glial fibrillary acid protein and vimentin in APP/PS1 mice increased the number of dystrophic neurites,(40,41) whereas astrocyte-producing kallikreinrelated peptidase 7 contributed to Ab…”
BackgroundNeuronal autophagy and intercellular regulation of homeostasis in the brain
Kulkarni, A., Chen, J., & Maday, S. (2018) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2018.02.008 · Cited by 125
Neuropathogenesis-on-chips for neurodegenerative diseases
Amartumur, S., Nguyen, H. M., Huynh, T., Kim, T. S., Woo, R., Oh, E., Kim, K. K., Lee, L. P., & Heo, C. (2024) · Nature Communications · doi:10.1038/s41467-024-46554-8 · Cited by 131
Astroglia and Tau: New Perspectives
Kovacs, G. G. (2020) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2020.00096 · Cited by 115
“Indeed, astrocytes may directly participate in APP metabolism and Aβ clearance (Ries and Sastre, 2016) but they seem to be implicated in neurofibrillary degeneration of AD where the number of activated astrocytes correlates not only with the burden of tangles (SerranoPozo et al., 2011) but with the…”
BackgroundXie, J., Gonzalez‐Carter, D., Tockary, T. A., Nakamura, N., Xue, Y., Nakakido, M., Akiba, H., Dirisala, A., Liu, X., Toh, K., et al. (2020) · ACS Nano · doi:10.1021/acsnano.9b09991 · Cited by 117
Wakabayashi, T., Yamaguchi, K., Matsui, K., Sano, T., Kubota, T., Hashimoto, T., Mano, A., Yamada, K., Matsuo, Y., Kubota, N., et al. (2019) · Molecular Neurodegeneration · doi:10.1186/s13024-019-0315-7 · Cited by 119
“In addition to the proteolytic digestion, the involvement of glial and vascular factors has been implicated in the clearance mechanisms of Aβ [52, 53].”
BackgroundFunctional Roles of the Interaction of APP and Lipoprotein Receptors
Pohlkamp, T., Wasser, C. R., & Herz, J. (2017) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2017.00054 · Cited by 92
“Lrp1 is also expressed in astrocytes and microglia where it is involved in Aβ-clearance (reviewed in Ries and Sastre, 2016).”
BackgroundAlzheimer’s Disease: Etiology, Neuropathology and Pathogenesis
Sheppard, O., & Coleman, M. P. (2020) · Exon Publications eBooks · doi:10.36255/exonpublications.alzheimersdisease.2020.ch1 · Cited by 127
“They often co-localize with neuronal debris and activated microglia and astrocytes (88), and first appear in the frontal, temporal and occipital lobes of the neocortex.”
BackgroundMicroglia and Astrocytes in Alzheimer’s Disease: Significance and Summary of Recent Advances
Deng, Q., Wu, C., Parker, E., Liu, T. C.-Y., Duan, R., & Yang, L. (2023) · Aging and disease · doi:10.14336/ad.2023.0907 · Cited by 102
Glia in neurodegeneration: Drivers of disease or along for the ride?
Gleichman, A. J., & Carmichael, S. T. (2020) · Neurobiology of Disease · doi:10.1016/j.nbd.2020.104957 · Cited by 90
Chidambaram, H., Das, R. R., & Chinnathambi, S. (2020) · Cell & Bioscience · doi:10.1186/s13578-020-00474-4 · Cited by 97
Das, T. K., & Ganesh, B. P. (2023) · Gut Microbes · doi:10.1080/19490976.2023.2206504 · Cited by 102
“Additionally, microglia have a significant role in Aβ clearance and degradation.(48) During microglial phagocytosis over time, the efficiency of microglia gradually declines Aβ clearance, which reduces Aβ proteolysis(49) and increases Aβ deposition and aggregation(50).”
BackgroundA review on ferulic acid and analogs based scaffolds for the management of Alzheimer’s disease
Singh, Y. P., Rai, H., Singh, G., Singh, G. K., Mishra, S. K., Kumar, S., Srikrishna, S., & Modi, G. P. (2021) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2021.113278 · Cited by 98
Fernandes, A., Ribeiro, A. R., Monteiro, M., Garcia, G., Vaz, A. R., & Brites, D. (2018) · Biochimie · doi:10.1016/j.biochi.2018.05.015 · Cited by 93
Resveratrol and Amyloid-Beta: Mechanistic Insights
Jia, Y., Wang, N., & Liu, X. (2017) · Nutrients · doi:10.3390/nu9101122 · Cited by 93
“Numerous pathways have been reported to play roles in Aβ clearance and degradation, including autophagic pathway and receptor-mediated endocytosis [6].”
BackgroundBogie, J. F. J., Hoeks, C., Schepers, M., Tiane, A., Cuypers, A., Leijten, F. P. J., Chintapakorn, Y., Suttiyut, T., Pornpakakul, S., Struik, D., et al. (2019) · Scientific Reports · doi:10.1038/s41598-019-41399-4 · Cited by 94
Gullotta, G. S., Costantino, G., Sortino, M. A., & Spampinato, S. F. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24119144 · Cited by 97
Protein astrogliopathies in human neurodegenerative diseases and aging
Kovács, G. G., Lee, V. M., & Trojanowski, J. Q. (2017) · Brain Pathology · doi:10.1111/bpa.12536 · Cited by 93
Spampinato, S. F., Merlo, S., Sano, Y., Kanda, T., & Sortino, M. A. (2017) · Journal of Neurochemistry · doi:10.1111/jnc.14068 · Cited by 90
Merlo, S., Spampinato, S. F., & Sortino, M. A. (2017) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2017.05.059 · Cited by 94
“In AD, both astrocytes and microglia have been specifically involved as mediators of multiple mechanisms of protection against Aβ toxicity and in Aβ removal from the brain (Ries and Sastre, 2016).”
Rifaai, R. A., Mokhemer, S. A., Saber, E. A., El‐Aleem, S. A. A., & El‐Tahawy, N. F. G. (2020) · Journal of Chemical Neuroanatomy · doi:10.1016/j.jchemneu.2020.101795 · Cited by 94
Pirzada, R. H., Javaid, N., & Choi, S. (2020) · Genes · doi:10.3390/genes11020131 · Cited by 84
CD36 in Alzheimer’s Disease: An Overview of Molecular Mechanisms and Therapeutic Targeting
Dobri, A.-M., Dudău, M., Enciu, A., & Hinescu, M. E. (2020) · Neuroscience · doi:10.1016/j.neuroscience.2020.11.003 · Cited by 83
“CD36-related Ab clearance by phagocytosis is another focus of microglia (Yamanaka et al., 2012; Ries and Sastre, 2016) and astrocyte (Jones et al.”
Candesartan ameliorates brain inflammation associated with Alzheimer's disease
Torika, N., Asraf, K., Apte, R. N., & Fleisher‐Berkovich, S. (2018) · CNS Neuroscience & Therapeutics · doi:10.1111/cns.12802 · Cited by 82
Ablation of reactive astrocytes exacerbates disease pathology in a model of Alzheimer's disease
Katsouri, L., Birch, A. M., Renziehausen, A. W. J., Zach, C., Aman, Y., Steeds, H., Bonsu, A., Palmer, E. O. C., Mirzaei, N., Ries, M., et al. (2020) · Glia · doi:10.1002/glia.23759 · Cited by 81
“…decreasing amyloid-related pathology was postulated based on the ability of these cells to promote clearance and degradation of amyloid peptides by producing degrading proteases, including insulin degrading enzyme (IDE), neprilysin, and metalloproteases (Ries & Sastre, 2016; Yamamoto et al., 2014).”
BackgroundSelf-citationLoeffler, D. A. (2023) · Journal of Alzheimer s Disease Reports · doi:10.3233/adr-230025 · Cited by 90
“and Sastre [58]) including low density lipoprotein”
Giordano-Kelhoffer, B., Lorca, C., March‐Llanes, J., Rábano, A., del Ser, T., Serra, A., & Gallart‐Palau, X. (2022) · Biomedicines · doi:10.3390/biomedicines10081803 · Cited by 89
Ullah, R., Park, T. J., Huang, X., & Kim, M. O. (2021) · Ageing Research Reviews · doi:10.1016/j.arr.2021.101451 · Cited by 78
“…al., 1996), Fc receptors (FcRs) (Bard et al., 2000a; Ries and Sastre, 2016), triggering receptor expressed on myeloid cells 2 (TREM2) (Kleinberger et al., 2014; Wang et al., 2015), and lipoprotein receptor-related proteins (LRPs) (N’Songo et al., 2013; Ries and Sastre, 2016; Zlokovic et al., 1996).”
BackgroundInfluentialPersistent repression of tau in the brain using engineered zinc finger protein transcription factors
Wegmann, S., DeVos, S. L., Zeitler, B., Marlen, K., Bennett, R. E., Perez-Rando, M., MacKenzie, D., Yu, Q., Commins, C., Bannon, R. N., et al. (2021) · Science Advances · doi:10.1126/sciadv.abe1611 · Cited by 77
“mRNA levels of the metalloendopeptidases neprilysin and endothelin-converting enzyme-1 (Ece1) that degrade intracellular neuronal A (42) did not change upon tau reduction in APP/PS1 mice (Fig.”
BackgroundRedox Signaling, Neuroinflammation, and Neurodegeneration
Aguilera, G., Colín-González, A. L., Rangel‐López, E., Chavarría, A., & Santamaría, A. (2017) · Antioxidants and Redox Signaling · doi:10.1089/ars.2017.7099 · Cited by 81
Hederagenin improves Alzheimer's disease through PPARα/TFEB-mediated autophagy
Xie, Z.-S., Zhao, J.-P., Wu, L.-M., Chu, S., Cui, Z.-H., Sun, Y.-R., Wang, H., Ma, H.-F., Ma, D.-R., Wang, P., et al. (2023) · Phytomedicine · doi:10.1016/j.phymed.2023.154711 · Cited by 77
Glial Draper Rescues Aβ Toxicity in aDrosophilaModel of Alzheimer's Disease
Ray, A., Speese, S. D., & Logan, M. A. (2017) · Journal of Neuroscience · doi:10.1523/jneurosci.0862-17.2017 · Cited by 79
“Microglia and astrocytes can engulf amyloid peptides, likely through an array of cell surface receptors that act in concert to recognize and internalize A in its various forms (Gold and El Khoury, 2015; Eugenin et al., 2016; Ries and Sastre, 2016), and, notably, many studies have identified AD susceptibility loci that…”
BackgroundDifferential regulation of autophagy during metabolic stress in astrocytes and neurons
Kulkarni, A., Dong, A., Kulkarni, V. V., Chen, J., Laxton, O., Anand, A., & Maday, S. (2019) · Autophagy · doi:10.1080/15548627.2019.1703354 · Cited by 81
The effect of aquaporin-4 mis-localization on Aβ deposition in mice
Pedersen, T. J., Keil, S. A., Han, W., Wang, M. X., & Iliff, J. J. (2023) · Neurobiology of Disease · doi:10.1016/j.nbd.2023.106100 · Cited by 75
“Several mechanisms have been implicated in the process of Aβ clearance, including local cellular degradation (Ries and Sastre, 2016), transporter-mediated transendothelial efflux(Deane et al.”
Autophagy in Astrocytes and its Implications in Neurodegeneration
Sung, K., & Jiménez-Sánchez, M. (2020) · Journal of Molecular Biology · doi:10.1016/j.jmb.2019.12.041 · Cited by 78
Neuroinflammatory Signaling in the Pathogenesis of Alzheimer’s Disease
Uddin, M. S., Kabir, M. T., Jalouli, M., Rahman, M. A., Jeandet, P., Behl, T., Alexiou, A. T., Albadrani, G. M., Abdel‐Daim, M. M., Perveen, A., et al. (2021) · Current Neuropharmacology · doi:10.2174/1570159x19666210826130210 · Cited by 76
“well as binds with Aβ Inconsistent, needs further studies [247, 249, 250]”
BackgroundYoun, K., Ho, C., & Jun, M. (2022) · Food Science and Human Wellness · doi:10.1016/j.fshw.2021.12.006 · Cited by 74
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
“, 2018) is strictly correlated with their aberrant activation during the AD progression (Bates et al., 2009; Ries and Sastre, 2016).”
BackgroundRoles of Cytokines in Alzheimer’s Disease
Chen, Z., Balachandran, Y. L., Chong, W. P., & Chan, K. W. Y. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25115803 · Cited by 75
“Furthermore, studies have shown that astrocytes in the AD brain secrete A β -degrading proteases, which cleave A β to inhibit insoluble aggregate formation and facilitate clearance through the blood–brain barrier (BBB) [4].”
BackgroundThe VCAM1–ApoE pathway directs microglial chemotaxis and alleviates Alzheimer’s disease pathology
Lau, S.-F., Wu, W., Wong, H. Y., Ouyang, L., Qiao, Y., Xu, J., Lau, J. H.-Y., Wong, C., Jiang, Y., Holtzman, D. M., et al. (2023) · Nature Aging · doi:10.1038/s43587-023-00491-1 · Cited by 70
Neurovascular unit dysfunction as a mechanism of seizures and epilepsy during aging
van Vliet, E. A., & Marchi, N. (2022) · Epilepsia · doi:10.1111/epi.17210 · Cited by 69
Naringenin promotes microglial M2 polarization and Aβ degradation enzyme expression
Yang, Z., Kuboyama, T., & Tohda, C. (2019) · Phytotherapy Research · doi:10.1002/ptr.6305 · Cited by 69
“Among microglia, M2 microglia reportedly express NEP and IDE and reduce Aβ plaques (Shimizu et al., 2008).”
BackgroundInfluentialResveratrol in experimental Alzheimer’s disease models: A systematic review of preclinical studies
Chen, J.-Y., Zhu, Q., Zhang, S., Ouyang, D., & Lu, J. (2019) · Pharmacological Research · doi:10.1016/j.phrs.2019.104476 · Cited by 67
Redox-Active Metal Ions and Amyloid-Degrading Enzymes in Alzheimer’s Disease
Kim, N., & Lee, H. J. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22147697 · Cited by 67
Davis, N., Mota, B. C., Stead, L., Palmer, E. O. C., Lombardero, L., Rodríguez-Puertas, R., de Paola, V., Barnes, S. J., & Sastre, M. (2021) · Journal of Neuroinflammation · doi:10.1186/s12974-021-02117-y · Cited by 65
Self-citation
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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