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Neuroprotective and neurotoxic properties of glial cells in the pathogenesis of Alzheimer's disease
Open accessAbstract
• Introduction • Innate immune response in the AD brain - Microglia - Astrocyte • Glial cells mediate the peripheral immune response in AD - Glial cell interaction with endothelial cells - Glial cell interaction with T cells • Glial cell activation as a therapeutic target in AD • Conclusion Alzheimer's disease (AD) affects more than 18 million people worldwide and is characterized by progressive memory deficits, cognitive impairment and personality changes. The main cause of AD is generally attributed to the increased production and accumulation of amyloid-β (Aβ), in association with neurofibrillary tangle (NFT) formation. Increased levels of pro-inflammatory factors such as cytokines and chemokines, and the activation of the complement cascade occurs in the brains of AD patients and contributes to the local inflammatory response triggered by senile plaque. The existence of an inflammatory component in AD is now well known on the basis of epidemiological findings showing a reduced prevalence of the disease upon long-term medication with anti-inflammatory drugs, and evidence from studies of clinical materials that shows an accumulation of activated glial cells, particularly microglia and astrocytes, in the same areas as amyloid plaques. Glial cells maintain brain plasticity and protect the brain for functional recovery from injuries. Dysfunction of glial cells may promote neurodegeneration and, eventually, the retraction of neuronal synapses, which leads to cognitive deficits. The focus of this review is on glial cells and their diversity properties in AD.
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“T-helper 1 cells can promote microglial cell activation through the secretion of IFN-γ, which also up-regulates the expression major histocompatibility complex class II molecules by microglial cells, thereby enhancing the interaction between T cells and microglial cells [164, 165].”
From PKR, the double stranded RNA‐dependent protein kinase as a critical target in Alzheimer's disease (2009) · cites this paper as [164]
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“T-helper 1 cells can promote microglial cell activation through the secretion of IFN-γ, which also up-regulates the expression major histocompatibility complex class II molecules by microglial cells, thereby enhancing the interaction between T cells and microglial cells [164, 165].”
From PKR, the double stranded RNA‐dependent protein kinase as a critical target in Alzheimer's disease (2009) · cites this paper as [164]
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“It is also known that glial cells can mediate the permeability of blood brain barrier to recruit specialized immune cells from the periphery such as T cells [164].”
From PKR, the double stranded RNA‐dependent protein kinase as a critical target in Alzheimer's disease (2009) · cites this paper as [164]
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“Dysfunction of glial cells may promote neurodegeneration and, eventually the retraction of neuronal synapses, which leads to cognitive deficits.((19)) The involvement of microglia and astrocytes in the onset and progress of neurodegenerative process in AD is becoming increasingly recognized.”
BackgroundWNT5A Signaling Contributes to Aβ-Induced Neuroinflammation and Neurotoxicity
Li, B., Zhong, L., Yang, X., Andersson, T., Huang, M., & Tang, S.-J. (2011) · PLoS ONE · doi:10.1371/journal.pone.0022920 · Cited by 81
“AD neuroinflammation is likely triggered by Ab-mediated activation of microglia and astrocytes [3,4, 12,13,14].”
BackgroundOh, J., Cho, W.-H., Barcelon, E. E., Kim, K. H., Hong, J., & Lee, S. J. (2022) · Scientific Reports · doi:10.1038/s41598-022-09410-7 · Cited by 74
Involvement of TRPV4 channels in Aβ40-induced hippocampal cell death and astrocytic Ca2+ signalling
Bai, J., & Lipski, J. (2014) · NeuroToxicology · doi:10.1016/j.neuro.2014.01.001 · Cited by 70
“, 2008), and are involved in AD-associated inflammation and astrogliosis (Selkoe, 2001; Mattson, 2004; Farfara et al., 2008).”
BackgroundTribouillard‐Tanvier, D., Striebel, J. F., Peterson, K. E., & Chesebro, B. W. (2009) · Journal of Virology · doi:10.1128/jvi.01413-09 · Cited by 73
“This conundrum has been faced in other neurodegenerative and neuroinflammatory diseases, such as Alzheimer’s disease (20), amyotrophic lateral sclerosis (4), Parkinson’s disease (51), and multiple sclerosis (13).”
BackgroundLana, D., Iovino, L., Nosi, D., Wenk, G. L., & Giovannini, M. G. (2016) · Experimental Gerontology · doi:10.1016/j.exger.2016.07.011 · Cited by 68
Wang, Y., Li, M., Tang, J., Song, M., Xu, X., Xiong, J., Li, J., & Bai, Y. (2011) · Endocrinology · doi:10.1210/en.2011-0145 · Cited by 66
Fitting, S., Zou, S., Chen, W., Vo, P., Hauser, K. F., & Knapp, P. E. (2010) · Journal of Proteome Research · doi:10.1021/pr900926n · Cited by 62
Guzmán, B. C., Chaffey, T. E., Palpagama, T. H., Waters, S., Boix, J., Tate, W. P., Peppercorn, K., Dragunow, M., Waldvogel, H. J., Faull, R. L. M., et al. (2020) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2020.552073 · Cited by 63
The effects of amyloid-β42 oligomer on the proliferation and activation of astrocytes in vitro
Hou, L., Liu, Y., Wang, X., Ma, H., He, J., Zhang, Y., Yu, C.-H., Guan, W., & Ma, Y.-H. (2011) · In Vitro Cellular & Developmental Biology - Animal · doi:10.1007/s11626-011-9439-y · Cited by 57
“Astrocytes, the biggest and the most abundant glial cell type in the central nervous system (Dan et al. 2008), play an important role in normal physiological functioning, e.g., the absorption of neurotransmitters, the synthesis and secretion of trophic factors, etc. (Takuma et al. 2004; Lü et al.…”
Backgroundγ‐Secretase component presenilin is important for microglia β‐amyloid clearance
Farfara, D., Trudler, D., Segev‐Amzaleg, N., Galron, R., Stein, R., & Frenkel, D. (2010) · Annals of Neurology · doi:10.1002/ana.22191 · Cited by 57
“ANNALS of Neurology 176 Volume 69, No. 1 Discussion We have demonstrated for the first time a dual role for c-secretase in the pathogenesis of AD.”
BackgroundInfluentialSelf-citationLam, D. Y., Jim, J., To, E. C., Rasmussen, C. A., Kaufman, P. L., & Matsubara, J. A. (2009) · Europe PMC (PubMed Central) · Cited by 57
The Potential Roles of Aquaporin 4 in Alzheimer’s Disease
Lan, Y., Zhao, J., Ma, T., & Li, S. (2015) · Molecular Neurobiology · doi:10.1007/s12035-015-9446-1 · Cited by 57
Oboh, G., Adebayo, A. A., Ademosun, A. O., & Olowokere, O. G. (2019) · NeuroToxicology · doi:10.1016/j.neuro.2019.12.008 · Cited by 56
Characterization of potent anticholinesterase plant oil based microemulsion
Chaiyana, W., Saeio, K., Hennink, W. E., & Okonogi, S. (2010) · International Journal of Pharmaceutics · doi:10.1016/j.ijpharm.2010.09.005 · Cited by 55
“This disease is associated with intellectual misfunction and ubsequent decline in cognitive, behavioral and motor functions Farfara et al., 2008).”
BackgroundGain in Brain Immunity in the Oldest-Old Differentiates Cognitively Normal from Demented Individuals
Katsel, P., Tan, W., & Haroutunian, V. H. (2009) · PLoS ONE · doi:10.1371/journal.pone.0007642 · Cited by 57
“One parsimonious interpretation of the expression of immune system marker genes in the oldest-old is that a robust immune system is essential for the maintenance of cognitive health to very old age [35,69,70], and that a failure of this system to respond to activating stimuli may contribute to the development of demen…”
BackgroundYaghmaei, P., Azarfar, K., Dezfulian, M., & Ebrahim‐Habibi, A. (2014) · DARU Journal of Pharmaceutical Sciences · doi:10.1186/2008-2231-22-24 · Cited by 55
“The flavonoid silibinin (or sylibin) [(2R,3R)-3,5,7-trihydroxy-2-[(2R,3R)-3-(4-hydroxy-3-methoxyphenyl)-2(hydroxy-methyl)-2,3-dihydrobenzo[b][1,4]doxin-6-yl] chroman-4-one] is the main compound of the herb milk thistle (Silybum marianum) extract (silymarin) [11].”
Microglial activation depends on beta‐amyloid conformation: role of the formylpeptide receptor 2
Heurtaux, T., Michelucci, A., Losciuto, S., Gallotti, C., Felten, P., Dorban, G., Grandbarbe, L., Morga, E., & Heuschling, P. (2010) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2010.06783.x · Cited by 55
“A large number of glial cell surface receptors are known to mediate interaction with the Ab peptide (Farfara et al. 2008).”
BackgroundRole of pattern recognition receptors of the neurovascular unit in inflamm-aging
Wilhelm, I., Nyúl-Tóth, Á., Kozma, M., Farkas, A. E., & Krizbai, I. A. (2017) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.00106.2017 · Cited by 56
“In addition, astrocytes are a common source of inflammatory mediators in brain pathologies (43).”
BackgroundYoshida, H., Meng, P., Matsumiya, T., Tanji, K., Hayakari, R., Xing, F., Wang, L. Y., Tsuruga, K., Tanaka, H., Mimura, J., et al. (2013) · Neuroscience Research · doi:10.1016/j.neures.2013.11.004 · Cited by 51
“neurodegenerative roles of astrocytes exposed to hypoxia or reoxygenation in patients with both AD and stroke (Farfara et al., 2008; Li et al., 2011; Yoshida et al., 2005), it is also a revealing fact that the A release from the cells treated with CA was suppressed under not only normoxia but also hypoxia or reoxygena…”
The neuroprotective effects of milk fat globule-EGF factor 8 against oligomeric amyloid β toxicity
Li, E., Noda, M., Doi, Y., Parajuli, B., Kawanokuchi, J., Sonobe, Y., Takeuchi, H., Mizuno, T., & Suzumura, A. (2012) · Journal of Neuroinflammation · doi:10.1186/1742-2094-9-148 · Cited by 54
“In neurodegenerative diseases, such as AD and Parkinson’s disease, microglia accumulate in lesions where they are thought to have both neurotoxic and neuroprotective functions [9].”
BackgroundUgolini, F., Lana, D., Nardiello, P., Nosi, D., Pantano, D., Casamenti, F., & Giovannini, M. G. (2018) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2018.00372 · Cited by 50
Zaheer, S. A., Thangavel, R., Wu, Y., Khan, M. M., Kempuraj, D., & Zaheer, A. (2012) · Neurochemical Research · doi:10.1007/s11064-012-0913-z · Cited by 50
“Activated glia are known to secrete proinflammatory cytokines and other toxic substances capable of causing neuronal death [26–28].”
Wu, Y., Pang, J., Peng, J., Cao, F., Vitek, M. P., Li, F., Jiang, Y. Q., & Sun, X. (2016) · Neuroscience Letters · doi:10.1016/j.neulet.2016.05.058 · Cited by 50
RetractedJiang, T., Luo, J., Pan, X., Zheng, H., Yang, H., Zhang, L., & Hu, X. (2021) · Life Sciences · doi:10.1016/j.lfs.2021.119526 · Cited by 51
Anwar, M. M. (2021) · Cell Biochemistry and Function · doi:10.1002/cbf.3673 · Cited by 54
Characterization of brain lesions in a mouse model of progressive multiple sclerosis
Levy, H., Assaf, Y., & Frenkel, D. (2010) · Experimental Neurology · doi:10.1016/j.expneurol.2010.08.017 · Cited by 50
“Glia cells maintain brain plasticity, protect the brain during functional recovery from injury, and, once properly activated, are the first defense against the pathologic abnormalities of neurodegenerative diseases (Farfara et al., 2008).”
Self-citationPKR, the double stranded RNA‐dependent protein kinase as a critical target in Alzheimer's disease
Morel, M., Couturier, J., Lafay‐Chebassier, C., Paccalin, M., & Page, G. (2009) · Journal of Cellular and Molecular Medicine · doi:10.1111/j.1582-4934.2009.00849.x · Cited by 47
“Thelper 1 cells can promote microglial cell activation through the secretion of IFN- , which also up-regulates the expression major histocompatibility complex class II molecules by microglial cells, thereby enhancing the interaction between T cells and microglial cells [164, 165].”
BackgroundSweepers in the CNS: Microglial Migration and Phagocytosis in the Alzheimer Disease Pathogenesis
Noda, M., & Suzumura, A. (2012) · International Journal of Alzheimer s Disease · doi:10.1155/2012/891087 · Cited by 52
“Microglia accumulate in the lesions of a variety of neurodegenerative disorders, such as Alzheimer’s disease (AD), Parkinson’s disease, and multiple sclerosis, and are thought to play both toxic and protective functions for neuronal survival [1].”
BackgroundNeurobiological aspects of Alzheimer's disease
Chopra, K., Misra, S., & Kuhad, A. (2011) · Expert Opinion on Therapeutic Targets · doi:10.1517/14728222.2011.557363 · Cited by 47
“Several amyloid peptides and APP can act as potent glial activators [75], and disruption of the APP gene and its proteolytic products delay and decrease microglial activation [76].”
BackgroundKovács, A., Saje, A., Wong, A. P., Szénási, G., Kiricsi, P., Szabó, É. R., Cooper, J. D., & Pearce, D. A. (2010) · Neuropharmacology · doi:10.1016/j.neuropharm.2010.10.010 · Cited by 46
“Activation of glial cells in general is a common event in neurodegenerative diseases (Danton and Dietrich, 2003; Farfara et al., 2008; Venneti et al., 2009), and several previous studies have shown that glial activation also occurs in Batten disease.”
In Vitro and In Vivo Activation of Astrocytes by Amyloid-β is Potentiated by Pro-Oxidant Agents
García‐Matas, S., de Vera, N., Aznar, A. O., Marimon, J. M., Adell, A., Planas, A. M., Cristòfol, R. M., & Sanfeliu, C. (2010) · Journal of Alzheimer s Disease · doi:10.3233/jad-2010-1365 · Cited by 45
“In advanced stages of AD pathology, these chronic astrocyte alterations of oxidative stress and inflammation will further impair neuron functionality and contribute to the degenerative process [67,68].”
Folch, J., Patraca, I., Martínez, N., Pedrós, I., Petrov, D., Ettcheto, M., Abad, S., Marin, M., Beas-Zarate, C., & Camins, A. (2015) · Life Sciences · doi:10.1016/j.lfs.2015.05.002 · Cited by 48
Lee, A. Y., Lee, M. H., Lee, S., & Cho, E. J. (2018) · Journal of Agricultural and Food Chemistry · doi:10.1021/acs.jafc.8b00836 · Cited by 43
Neuron‐glia interactions: Molecular basis of alzheimer’s disease and applications of neuroproteomics
Ibrahim, A. M., Pottoo, F. H., Dahiya, E. S., Khan, F. A., & Kumar, J. B. S. (2020) · European Journal of Neuroscience · doi:10.1111/ejn.14838 · Cited by 46
“…microglia, reactive astrocytes, progressive synaptic dysfunction and neuronal death in advanced chronic states found majorly in the hippocampus points towards AD (Bedner et al., 2015; Farfara et al., 2008; Hemonnot, Hua, Ulmann, & Hirbec, 2019; Kosik, 1991; Sharoar, Hu, Ma, Zhu, & Yan, 2019).”
BackgroundMoreno‐González, I., Baglietto‐Vargas, D., Sanchez-Varo, R. M., Jiménez, S., Trujillo‐Estrada, L., Sánchez‐Mejías, E., del Río, J. C., Torres, M., Romero‐Acebal, M., Ruano, D., et al. (2009) · Journal of Alzheimer s Disease · doi:10.3233/jad-2009-1192 · Cited by 42
Age-dependent therapeutic effect of memantine in a mouse model of juvenile Batten disease
Kovács, A., Saje, A., Wong, A. P., Ramji, S., Cooper, J. D., & Pearce, D. A. (2012) · Neuropharmacology · doi:10.1016/j.neuropharm.2012.05.040 · Cited by 42
“Activation of astrocytes and microglial cells is a fairly common event in neurodegenerative disorders including Batten disease (Danton and Dietrich, 2003; Farfara et al., 2008; Venneti et al., 2009).”
Background
Metadata
- Authors
- Farfara, D., Lifshitz, V., & Frenkel, D.
- Affiliations
- Tel Aviv University (IL)
- Corresponding author
- Frenkel, D.
- Venue
- Journal of Cellular and Molecular Medicine
- Publisher
- Wiley
- Published
- 2008-05-21
- Volume
- 12
- Issue
- 3
- Pages
- 762-780
- ISSN
- 1582-1838 (ISSN-L)
- 1582-4934
- PMC
- PMC4401126
- OpenAlex
- W2022388884
- Cited by
- 216
- References
- 202
- Citations by year
- 2026: 3 · 2025: 7 · 2024: 8 · 2023: 7 · 2022: 7 · 2021: 10 · 2020: 13 · 2019: 5 · 2018: 7 · 2017: 9 · 2016: 7 · 2015: 8 · 2014: 15 · 2013: 15 · 2012: 20
- FWCI
- 2.12
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Cellular and Molecular Medicine (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
- Keywords
- Alzheimer's disease, glial cells, microglia, astrocytes, neuroinflammation, innate immune response, amyloid-beta, neurofibrillary tangles, amyloid plaques, complement system, cytokines and chemokines, neuroprotection, neurotoxicity, neurodegeneration, anti-inflammatory therapy
- MeSH terms
- Alzheimer Disease, Amyloid, Animals, Astrocytes, Brain, Disease Models, Animal, Humans, Models, Neurological, Synaptic Transmission, Synapses, T-Lymphocytes, Amyloid beta-Peptides, Microglia, Endothelial Cells, Plaque, Amyloid
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