Microglia in Alzheimer’s disease

Hansen, David V.; Hanson, Jesse E.; Sheng, Morgan

doi:10.1083/jcb.201709069

Cited by 1,346 publications

(1,157 citation statements)

References 183 publications

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“…39,[42][43][44] Recently, emerging evidence supports the hypothesis that the dysfunction of microglia, the counterpart of macrophages in the brain, plays important roles in the pathogenesis of AD. [45][46][47] In the present study, levels of the microglial marker CD11b were reduced in ob/ob and App NL-F/wt knock-in; ob/ob mice at both 6 and 18 months. Interestingly, the expression of Trem2 and its partner Dap12 were also reduced in these mice.…”

Section: Discussionsupporting

confidence: 53%

Increased levels of Aβ42 decrease the lifespan ofob/obmice with dysregulation of microglia and astrocytes

et al. 2019

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Abbreviations: Aβ, β-amyloid; AD, Alzheimer's disease; APP, amyloid precursor protein; CNS, central nervous system; DEA, diethylamine; GFAP, glial fibrillary acidic protein; INSR, insulin receptor; IRS1, insulin receptor substrate-1; IRS2, insulin receptor substrate-2; PDK1, pyruvate dehydrogenase kinase 1; PSD95, post-synaptic density protein 95; SYT1, synaptotagmin 1; NF-H, neurofilament heavy chain. AbstractClinical studies have indicated that obesity and diabetes are associated with Alzheimer's disease (AD) and neurodegeneration. Although the mechanisms underlying these associations remain elusive, the bidirectional interactions between obesity/ diabetes and Alzheimer's disease (AD) may be involved in them. Both obesity/ diabetes and AD significantly reduce life expectancy. We generated App NL-F/wt knock-in; ob/ob mice by crossing App NL-F/wt knock-in mice and ob/ob mice to investigate whether amyloid-β (Aβ) affects the lifespan of ob/ob mice. App NL-F/wt knock-in; ob/ob mice displayed the shortest lifespan compared to wild-type mice, App NL-F/wt knockin mice, and ob/ob mice. Notably, the Aβ42 levels were increased at minimum levels before deposition in App NL-F/wt knock-in mice and App NL-F/wt knock-in; ob/ob mice at 18 months of age. No differences in the levels of several neuronal markers were observed between mice at this age. However, we observed increased levels of glial fibrillary acidic protein (GFAP), an astrocyte marker, in App NL-F/wt knock-in; ob/ob mice, while the levels of several microglial markers, including CD11b, TREM2, and DAP12, were decreased in both ob/ob mice and App NL-F/wt knock-in; ob/ob mice. The increase in GFAP levels was not observed in young App NL-F/wt knock-in; ob/ob mice. |SHINOHARA et Al.

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Section: Discussionsupporting

confidence: 53%

Increased levels of Aβ42 decrease the lifespan ofob/obmice with dysregulation of microglia and astrocytes

et al. 2019

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“…Apart from beneficial roles in the development of CNS, microglia can be widely involved in various types of neurological disorders, including stroke (Guruswamy & ElAli, ; Kronenberg et al, ), multiple sclerosis (MS) (Bogie, Stinissen, & Hendriks, ; Luo et al, ), AD (Hansen, Hanson, & Sheng, ; Sarlus & Heneka, ), PD (Subramaniam & Federoff, ), sleep disorders (Nadjar, Wigren, & Tremblay, ), amyotrophic lateral sclerosis (ALS) (Geloso et al, ; Liu & Wang, ), Huntington's disease (H. M. Yang, Yang, Huang, Tang, & Guo, ), epilepsy (Eyo, Murugan, & Wu, ; Zhao, Liao, et al, ), gliomas (Hambardzumyan, Gutmann, & Kettenmann, ; Schiffer, Mellai, Bovio, & Annovazzi, ), Prion diseases (Aguzzi & Zhu, ; Obst, Simon, Mancuso, & Gomez‐Nicola, ), psychiatric disorders (Mondelli, Vernon, Turkheimer, Dazzan, & Pariante, ; Prinz & Priller, ; Setiawan et al, ; Singhal & Baune, ), neuropathic pain (Inoue & Tsuda, ; Peng et al, ), adrenomyeloneuropathy (Gong et al, ), and traumatic brain injury (Donat, Scott, Gentleman, & Sastre, ). In general, microglia can be rapidly activated depending upon different stimulatory contexts and environmental changes through diverse molecular and cellular programs, subsequently transforming into the activated state and enhancing the expression of the Toll‐like receptors which sensitively bind microbial structures (Arcuri et al, ).…”

Section: The Role Of Microglia In Neurological Diseases: Friend or Foe?mentioning

confidence: 99%

Enforced microglial depletion and repopulation as a promising strategy for the treatment of neurological disorders

Han

Zhu

Zhang

et al. 2018

Glia

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Microglia are prominent immune cells in the central nervous system (CNS) and are critical players in both neurological development and homeostasis, and in neurological diseases when dysfunctional. Our previous understanding of the phenotypes and functions of microglia has been greatly extended by a dearth of recent investigations. Distinct genetically defined subsets of microglia are now recognized to perform their own independent functions in specific conditions. The molecular profiling of single microglial cells indicates extensively heterogeneous reactions in different neurological disorders, resulting in multiple potentials for crosstalk with other kinds of CNS cells such as astrocytes and neurons. In settings of neurological diseases it could thus be prudent to establish effective cell‐based therapies by targeting entire microglial networks. Notably, activated microglial depletion through genetic targeting or pharmacological therapies within a suitable time window can stimulate replenishment of the CNS niche with new microglia. Additionally, enforced repopulation through provision of replacement cells also represents a potential means of exchanging dysfunctional with functional microglia. In each setting the newly repopulated microglia might have the potential to resolve ongoing neuroinflammation. In this review, we aim to summarize the most recent knowledge of microglia and to highlight microglial depletion and subsequent repopulation as a promising cell replacement therapy. Although glial cell replacement therapy is still in its infancy and future translational studies are still required, the approach is scientifically sound and provides new optimism for managing the neurotoxicity and neuroinflammation induced by activated microglia.

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“…A distinct microglial subtype, termed "dark microglia," has also been characterized in a murine model of AD. These cells closely surround synaptic clefts in amyloid plaques (78) and have been proposed to play a role in the pathologic synaptic stripping in AD (78,79).…”

Section: Microglia Heterogeneity and Admentioning

confidence: 99%

“…Microglia pathways have been implicated in a number of studies relating to both AD pathogenesis and risk. A significant proportion of genes identified in genome-wide association studies as being associated with risk for sporadic AD are involved in microglial functions [reviewed elsewhere (79)]. A rare variant of a microglial-expressed gene, TREM2, is associated with a significantly increased risk for developing AD (80,81).…”

Section: Microglia Heterogeneity and Admentioning

confidence: 99%

Unravelling the glial response in the pathogenesis of Alzheimer's disease

2018

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Alzheimer's disease is a progressive, incurable neurodegenerative disease targeting specific neuronal populations within the brain while neighboring neurons appear unaffected. The focus for defining mechanisms has therefore been on the pathogenesis in affected neuronal populations and developing intervention strategies to prevent their cell death. However, there is growing recognition of the importance of glial cells in the development of pathology. Determining exactly how glial cells are involved in the disease process and the susceptibility of the aging brain provides unprecedented challenges. The present review examines recent studies attempting to unravel the glial response during the course of disease and how this action may dictate the outcome of neurodegeneration. The importance of regional heterogeneity of glial cells within the CNS during healthy aging and disease is examined to understand how the glial cells may contribute to neuronal susceptibility or resilience during the neurodegenerative process.—Alibhai, J. D., Diack, A. B., Manson, J. C. Unravelling the glial response in the pathogenesis of Alzheimer's disease. 32, 5766–5777 (2018). http://www.fasebj.org

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Microglia in Alzheimer’s disease

Abstract: Hansen et al. review the potential dual helpful and harmful roles of microglia in the development and progression of Alzheimer’s disease.

Cited by 1,346 publications

References 183 publications

Increased levels of Aβ42 decrease the lifespan ofob/obmice with dysregulation of microglia and astrocytes

Increased levels of Aβ42 decrease the lifespan ofob/obmice with dysregulation of microglia and astrocytes

Enforced microglial depletion and repopulation as a promising strategy for the treatment of neurological disorders

Unravelling the glial response in the pathogenesis of Alzheimer's disease

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