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Microglia in the aging brain: relevance to neurodegeneration
Open accessAbstract
Microglia cells are the brain counterpart of macrophages and function as the first defense in the brain. Although they are neuroprotective in the young brain, microglia cells may be primed to react abnormally to stimuli in the aged brain and to become neurotoxic and destructive during neurodegeneration. Aging-induced immune senescence occurs in the brain as age-associated microglia senescence, which renders microglia to function abnormally and may eventually promote neurodegeneration. Microglia senescence is manifested by both morphological changes and alterations in immunophenotypic expression and inflammatory profile. These changes are likely caused by microinvironmental factors, but intrinsic factors cannot yet be completely excluded. Microglia senescence appears to underlie the switching of microglia from neuroprotective in the young brain to neurotoxic in the aged brain. The hypothesis of microglia senescence during aging offers a novel perspective on their roles in aging-related neurodegeneration. In Parkinson's disease and Alzheimer's disease, over-activation of microglia may play an active role in the pathogenesis because microglia senescence primes them to be neurotoxic during the development of the diseases.
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“The ageing brain is also characterised by structural and functional changes to microglial cells, which are the resident immune cell population of the central nervous system (CNS) and are the CNS equivalent of macrophages. They are activated by brain injury and local and systemic inflammation and become primed (hyper-responsive) to small stimuli with ageing, which can potentially cause damage and”
From Frailty in elderly people (2013) · cites this paper as [26]
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BackgroundHIV TAT-mediated microglial senescence: Role of SIRT3-dependent mitochondrial oxidative stress
Thangaraj, A., Chivero, E. T., Tripathi, A., Singh, S., Niu, F., Guo, M.-L., Pillai, P., Periyasamy, P., & Buch, S. (2021) · Redox Biology · doi:10.1016/j.redox.2020.101843 · Cited by 76
Repeated Lipopolysaccharide Stimulation Induces Cellular Senescence in BV2 Cells
Yu, H.-M., Zhao, Y.-M., Luo, X.-G., Feng, Y., Ren, Y., Shang, H., He, Z.-Y., Luo, X.-M., Chen, S.-D., & Wang, X.-Y. (2012) · Neuroimmunomodulation · doi:10.1159/000330254 · Cited by 76
Self-citationBeier, E. E., Neal, M. P., Alam, G., Edler, M. K., Wu, L., & Richardson, J. R. (2017) · Neurobiology of Disease · doi:10.1016/j.nbd.2017.08.009 · Cited by 78
SARS-CoV-2: is there neuroinvasion?
McQuaid, C., Brady, M., & Deane, R. (2021) · Fluids and Barriers of the CNS · doi:10.1186/s12987-021-00267-y · Cited by 72
Turrini, S., Wong, B., Eldaief, M. C., Press, D. Z., Sinclair, D. A., Koch, G., Avenanti, A., & Santarnecchi, E. (2023) · Ageing Research Reviews · doi:10.1016/j.arr.2023.101939 · Cited by 88
“While microglia cells have a neuroprotective role in the young brain, multiple studies have shown that they gradually transition to a chronically activated and neurotoxic state in older adults (Luo et al., 2010), irrespective of their cognitive status (Gefen, 2019; Niraula et al., 2017).”
BackgroundHilal, S., Ikram, M. A., Verbeek, M. M., Franco, O. H., Stoops, E., Vanderstichele, H., Niessen, W. J., & Vernooij, M. W. (2018) · Stroke · doi:10.1161/strokeaha.118.022317 · Cited by 71
de Hoz, R., Ramirez, A. I., Gonzalez‐Martin, R., Ajoy, D., Rojas, B., Salobrar‐García, E., Valiente‐Soriano, F. J., Avilés‐Trigueros, M., Villegas‐Pérez, M. P., Vidal‐Sanz, M., et al. (2018) · Experimental Eye Research · doi:10.1016/j.exer.2018.03.006 · Cited by 71
“…can act as antigen-presenting cells, and can transform into phagocytes (Karlstetter et al., 2015; Karlstetter et al., 2015; Kettenmann et al., 2011; Kettenmann et al., 2011; Luo et al., 2010; Luo et al., 2010; Ramírez et al., 2015; Ransohoff and Perry, 2009; Kezic et al., 2013; Wang et al., 2017).”
BackgroundDas, R. R., & Chinnathambi, S. (2020) · Neuroscience · doi:10.1016/j.neuroscience.2020.09.024 · Cited by 71
Phenotypic and functional differences between senescent and aged murine microglia
Stojiljkovic, M. R., Ain, Q., Bondeva, T., Heller, R., Schmeer, C., & Witte, O. W. (2019) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2018.10.007 · Cited by 71
Desplats, P., Gutierrez, A. M., Antonelli, M. C., & Frasch, M. G. (2019) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2019.10.013 · Cited by 74
Huang, X., Chen, Y., Zhang, H., Ma, Q., Zhang, Y., & Xu, H. (2011) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2011.10.007 · Cited by 68
“Aβ deposits also trigger microglia-mediated neuroinflammation, postulated to contribute to the pathogenesis and progression of AD (Giulian et al., 1995; Minghetti, 2005; Floden et al., 2005; Luo et al., 2010).”
BackgroundMicroglia and Synapse: Interactions in Health and Neurodegeneration
Šišková, Z., & Tremblay, M.-È. (2013) · Neural Plasticity · doi:10.1155/2013/425845 · Cited by 80
Singh, Y. P., Pandey, A., Vishwakarma, S., & Modi, G. P. (2018) · Molecular Diversity · doi:10.1007/s11030-018-9878-4 · Cited by 69
IP3, a small molecule with a powerful message
Decrock, E., Bock, M. D., Wang, N., Gadicherla, A. K., Bol, M., Delvaeye, T., Vandenabeele, P., Vinken, M., Bultynck, G., Krysko, D. V., et al. (2013) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2012.12.016 · Cited by 64
Das, R. R., & Chinnathambi, S. (2021) · Traffic · doi:10.1111/tra.12784 · Cited by 62
“and invasion can be a determinant of altered function in CNS injury and inflammation.(71,72) The soluble but reactive Tau oligomers can readily diffuse through brain parenchyma and attracts microglial chemotaxis.”
BackgroundAzevedo, E. P., Ledo, J. H., Barbosa, G., Sobrinho, M., Diniz, L. P., da Fonseca, A. C. C., Gomes, F. C. A., Romão, L. F., Lima, F. R. S., Palhano, F. L., et al. (2013) · Cell Death and Disease · doi:10.1038/cddis.2013.325 · Cited by 66
“However, chronically activated microglia may initiate inflammatory processes that lead to neuronal dysfunction and damage.(15,16) Thus, tight regulation of”
BackgroundCouturier, J., Paccalin, M., Morel, M., Terro, F., Milin, S., Pontcharraud, R., Fauconneau, B., & Page, G. (2011) · Journal of Neuroinflammation · doi:10.1186/1742-2094-8-72 · Cited by 65
“Recent papers have underlined the senescence of microglia in AD, with loss of their neuroprotective properties, preceding the onset of tau pathology [90], suggesting that breakdown of the brain’s immune system may be an important factor in the development of neurodegeneration [91].”
BackgroundMander, B. A., Dave, A., Lui, K. K., Sprecher, K. E., Berisha, D. E., Chappel-Farley, M. G., Chen, I. Y., Riedner, B. A., Heston, M. B., Suridjan, I., et al. (2022) · SLEEP · doi:10.1093/sleep/zsac135 · Cited by 62
Centenary of the death of Elie Metchnikoff: a visionary and an outstanding team leader
Cavaillon, J., & Legout, S. (2016) · Microbes and Infection · doi:10.1016/j.micinf.2016.05.008 · Cited by 65
“Microglia senescence appears to underlie the switching of microglia from neuroprotective in the young brain to neurotoxic in the aged brain [85].”
LncRNA-OIS1 regulates DPP4 activation to modulate senescence induced by RAS
Li, L., Breugel, P. C. V., Loayza‐Puch, F., Ugalde, A. P., Korkmaz, G., Messika-Gold, N., Han, R., Lopes, R., Barberà, E. P., Teunissen, H., et al. (2018) · Nucleic Acids Research · doi:10.1093/nar/gky087 · Cited by 58
Targeting normal and cancer senescent cells as a strategy of senotherapy
Sikora, E., Bielak-Żmijewska, A., & Mosieniak, G. (2019) · Ageing Research Reviews · doi:10.1016/j.arr.2019.100941 · Cited by 59
Amelioration of LPS-Induced Inflammation Response in Microglia by AMPK Activation
Chen, C.-C., Lin, J., Cheng, Y.-F., Kuo, C., Huang, C.-F., Kao, S., Liang, Y.-J., Cheng, C., & Chen, H.-M. (2014) · BioMed Research International · doi:10.1155/2014/692061 · Cited by 56
Neuroprotection for Ischemic Stroke: Moving Past Shortcomings and Identifying Promising Directions
Turner, R. C., Lucke-Wold, B. P., Lucke-Wold, N., Elliott, A. S., Logsdon, A. F., Rosen, C. L., & Huber, J. D. (2013) · International Journal of Molecular Sciences · doi:10.3390/ijms14011890 · Cited by 52
“These cytokines activate neurodegenerative pathways [21].”
Effects of acoustic trauma on the auditory system of the rat: The role of microglia
Baizer, J. S., Wong, K. M., Manohar, S., Hayes, S. H., Ding, D., Dingman, R., & Salvi, R. (2015) · Neuroscience · doi:10.1016/j.neuroscience.2015.07.004 · Cited by 53
“…may have a “destroyer” role; actively facilitating the degenerative processes of Alzheimer’s disease, amyotrophic lateral sclerosis, multiple sclerosis and other neurodegenerative disorders (Barger and Harmon, 1997, Streit, 2004, Ponomarev et al., 2006, Block et al., 2007, Luo et al., 2010).”
BackgroundTheoharides, T. C., Twahir, A., & Kempuraj, D. (2023) · Annals of Allergy Asthma & Immunology · doi:10.1016/j.anai.2023.10.032 · Cited by 58
Design, synthesis, and evaluation of small molecule Hsp90 probes
Taldone, T., Zatorska, D., Patel, P. D., Zong, H., Rodina, A., Ahn, J. H., Moulick, K., Guzmán, M. L., & Chiosis, G. (2011) · Bioorganic & Medicinal Chemistry · doi:10.1016/j.bmc.2011.03.013 · Cited by 51
Epigenetic assimilation in the aging human brain
Oh, G., Ebrahimi, S. B., Wang, S.-C., Cortese, R., Kaminsky, Z. A., Gottesman, I. I., Burke, J. R., Plassman, B. L., & Petronis, A. (2016) · Genome biology · doi:10.1186/s13059-016-0946-8 · Cited by 54
“The changes observed in the AD brain samples, and perhaps in the aging brains in general [40], could be related to disproportional loss of neurons compared with neuroglia observed in AD [41].”
BackgroundResultSong, I., Chung, S., Kim, Y., & Maeng, L.-S. (2015) · International Journal of Medical Sciences · doi:10.7150/ijms.12742 · Cited by 50
Activated Microglia in Cortical White Matter Across Cognitive Aging Trajectories
Gefen, T. D., Kım, G., Bolbolan, K., Geoly, A. D., Ohm, D. T., Oboudiyat, C., Shahidehpour, R. K., RADEMAKER, A. W., Weıntraub, S., Bigio, E. H., et al. (2019) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2019.00094 · Cited by 50
Free radical biology in neurological manifestations: mechanisms to therapeutics interventions
Tripathi, R. S., Gupta, R. V., Sahu, M., Srivastava, D., Das, A., Ambasta, R. K., & Kumar, P. (2021) · Environmental Science and Pollution Research · doi:10.1007/s11356-021-16693-2 · Cited by 54
“Activated microglia have been reported in numerous neurodegenerative diseases where aging impairs microglial functions due to increased sensitivity towards pro-inflammatory signals (Luo et al. 2010; von Bernhardi et al. 2010).”
BackgroundTubby regulates microglial phagocytosis through MerTK
Caberoy, N. B., Alvarado, G., & Li, W. (2012) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2012.07.009 · Cited by 47
“Microglial senescence with increased susceptibility to activation has been implicated in age-related neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease (Lee and Landreth, 2010; Luo et al., 2010; von Bernhardi et al., 2010).”
BackgroundChen, X., Feng, Y., Quinn, R. J., Pountney, D. L., Richardson, D. R., Mellick, G. D., & Ma, L. (2023) · Pharmacological Reviews · doi:10.1124/pharmrev.122.000743 · Cited by 44
“…channels is the hallmark of overactivated microglia (Kettenmann et al., 1993; Noren-berg et al., 1994; Nguyen et al., 2017; Di Lucente et al., 2018; Sarkar et al., 2020), while uncontrolled microglial activities aggravate the neurodegeneration in PD (Luo et al., 2010; Badanjak et al., 2021).”
BackgroundInhibition of mitochondrial fission attenuates Aβ-induced microglia apoptosis
Xie, N., Wang, C., Lian, Y., Wu, C., Zhang, H., & Zhang, Q. (2013) · Neuroscience · doi:10.1016/j.neuroscience.2013.10.011 · Cited by 44
Aging and Neurodegeneration: A Tangle of Models and Mechanisms
Chakrabarti, S., & Mohanakumar, K. P. (2016) · Aging and Disease · doi:10.14336/ad.2016.0312 · Cited by 46
“For example, mitochondrial dysfunction, oxidative stress, inflammatory response and proteotoxicity are common themes in AD and brain aging [2,3,4,5].”
BackgroundThe effect of aged microglia on synaptic impairment and its relevance in neurodegenerative diseases
Triviño, J. J., & von Bernhardi, R. (2021) · Neurochemistry International · doi:10.1016/j.neuint.2021.104982 · Cited by 43
The Role of Microglia in Perioperative Neurocognitive Disorders
Fan, W., Mai, L., Zhu, X. M., Huang, F., & He, H. (2020) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2020.00261 · Cited by 42
The Interaction of Diet and Mitochondrial Dysfunction in Aging and Cognition
Kaliszewska, A., Allison, J., Martini, M., & Arias, N. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22073574 · Cited by 52
Albornoz, E. A., Woodruff, T. M., & Gordon, R. (2018) · Experientia supplementum · doi:10.1007/978-3-319-89390-7_3 · Cited by 42
Benfotiamine upregulates antioxidative system in activated BV-2 microglia cells
Bozic, I. D., Savić, D. Z., Stevanović, I. D., Peković, S., Nedeljković, N., & Lavrnja, I. C. (2015) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2015.00351 · Cited by 44
“These data together imply that benfotiamine exhibits significant antioxidative activity in BV-2 cells.”
BackgroundBowirrat, A. (2022) · Journal of Personalized Medicine · doi:10.3390/jpm12111817 · Cited by 46
“The effect of aging on microglial activity is extremely important, as it is known that aging has an inverse relationship with the activity of the microglia, and aging causes changes in gene expressions, dystrophic microglia, and abnormal cytoplasmic formation, decreasing the microglia’s elasticity and lowering the act…”
BackgroundImpact of Long-Term RF-EMF on Oxidative Stress and Neuroinflammation in Aging Brains of C57BL/6 Mice
Jeong, Y. J., Son, Y., Han, N.-K., Choi, H., Pack, J., Kim, N., Lee, Y., & Lee, H. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19072103 · Cited by 44
“It is speculated that any changes in glial activation during aging are key components that influence the pathogenesis of neurodegeneration [36].”
Zhao, Y., & Yang, G. (2021) · Neurochemistry International · doi:10.1016/j.neuint.2021.104974 · Cited by 41
Metadata
- Authors
- Luo, X.-G., Ding, J.-Q., & Chen, S.-D.
- Venue
- Molecular Neurodegeneration
- Published
- 2010-03-24
- Volume
- 5
- Issue
- 1
- Pages
- 12-12
- ISSN
- 1750-1326 (ISSN-L)
- PMC
- PMC2852379
- OpenAlex
- W2156427445
- Cited by
- 236
- References
- 85
- Citations by year
- 2026: 7 · 2025: 12 · 2024: 10 · 2023: 11 · 2022: 17 · 2021: 14 · 2020: 15 · 2019: 11 · 2018: 20 · 2017: 13 · 2016: 18 · 2015: 19 · 2014: 12 · 2013: 22 · 2012: 15
- FWCI
- 10.86
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- Molecular Neurodegeneration (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
- Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
- Keywords
- microglia, brain aging, neurodegeneration, microglial senescence, immunosenescence, neuroinflammation, neuroprotection, Parkinson's disease, Alzheimer's disease, microglial activation, neurotoxicity
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