Replicative senescence dictates the emergence of disease-associated microglia and contributes to Aβ pathology

Hu, Yanling; Fryatt, Gemma L.; Ghorbani, Mohammadmersad; Obst, Juliane; Menassa, David A.; Margarida, Maria; Muntslag, Tim A.O.; Olmos-Alonso, Adrián; Guerrero-Carrasco, Monica; Thomas, Daniel; Cragg, Mark S.; Gómez-Nicola, Diego

doi:10.1016/j.celrep.2021.109228

Cited by 154 publications

(168 citation statements)

References 56 publications

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“…It is possible that there are mechanisms in place by which the brain is capable of sensing and responding to abnormal microglial density. It is also possible that CSF1-induced proliferation eventually leads to microglial senescence [ 32 ], or that older microglia respond differently to the CSF1 mitogenic signal. Additional studies will be required to distinguish between these possibilities.…”

Section: Discussionmentioning

confidence: 99%

Microglial responses to CSF1 overexpression do not promote the expansion of other glial lineages

Maklakova

Litscher

et al. 2021

J Neuroinflammation

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Background Colony-stimulating factor 1 (CSF1) expression in the central nervous system (CNS) increases in response to a variety of stimuli, and CSF1 is overexpressed in many CNS diseases. In young adult mice, we previously showed that CSF1 overexpression in the CNS caused the proliferation of IBA1+ microglia without promoting the expression of M2 polarization markers. Methods Immunohistochemical and molecular analyses were performed to further examine the impact of CSF1 overexpression on glia in both young and aged mice. Results As CSF1 overexpressing mice age, IBA1+ cell numbers are constrained by a decline in proliferation rate. Compared to controls, there were no differences in expression of the M2 markers ARG1 and MRC1 (CD206) in CSF1 overexpressing mice of any age, indicating that even prolonged exposure to increased CSF1 does not impact M2 polarization status in vivo. Moreover, RNA-sequencing confirmed the lack of increased expression of markers of M2 polarization in microglia exposed to CSF1 overexpression but did reveal changes in expression of other immune-related genes. Although treatment with inhibitors of the CSF1 receptor, CSF1R, has been shown to impact other glia, no increased expression of oligodendrocyte lineage or astrocyte markers was observed in CSF1 overexpressing mice. Conclusions Our study indicates that microglia are the primary glial lineage impacted by CSF1 overexpression in the CNS and that microglia ultimately adapt to the presence of the CSF1 mitogenic signal.

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Section: Discussionmentioning

confidence: 99%

Microglial responses to CSF1 overexpression do not promote the expansion of other glial lineages

Maklakova

Litscher

et al. 2021

J Neuroinflammation

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“…Accumulative studies have shown microglia-mediated regulation of plaque deposition and/or p-tau propagation by CSF1R inhibitors. For example, the prevention of early microglial proliferation by a CSF1R inhibitor (GW2580) hinders the development of senescence and disease-associated microglia, impairing the accumulation of Aβ, as well as associated neuritic and synaptic damage ( Hu et al, 2021 ). Moreover, CSF1R-inhibition-mediated microglia deletion protects against plaque-dependent perineuronal nets (PNNs) loss in the AD brain ( Crapser et al, 2020 ), prevents plaque deposition, and improves cognition in different AD-related mouse models ( Dagher et al, 2015 ; Olmos-Alonso et al, 2016 ; Sosna et al, 2018 ; Spangenberg et al, 2019 ).…”

Section: Csf1r In Neurodegenerative Diseasesmentioning

confidence: 99%

Insights Into the Role of CSF1R in the Central Nervous System and Neurological Disorders

Duan

Wang

et al. 2021

Front. Aging Neurosci.

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The colony-stimulating factor 1 receptor (CSF1R) is a key tyrosine kinase transmembrane receptor modulating microglial homeostasis, neurogenesis, and neuronal survival in the central nervous system (CNS). CSF1R, which can be proteolytically cleaved into a soluble ectodomain and an intracellular protein fragment, supports the survival of myeloid cells upon activation by two ligands, colony stimulating factor 1 and interleukin 34. CSF1R loss-of-function mutations are the major cause of adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) and its dysfunction has also been implicated in other neurodegenerative disorders including Alzheimer’s disease (AD). Here, we review the physiological functions of CSF1R in the CNS and its pathological effects in neurological disorders including ALSP, AD, frontotemporal dementia and multiple sclerosis. Understanding the pathophysiology of CSF1R is critical for developing targeted therapies for related neurological diseases.

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“…Rare genetic variants of TREM2 have been identified to impair microglial function and hence identified as risk factors for late-onset AD (Gratuze et al, 2018). It was also reported that replicative senescence of microglia leads to formation of DAM and contributes to early Aβ pathology (Hu et al, 2021).…”

Section: Role Of Microglia In Alzheimer's Disease-associated Neuroinflammationmentioning

confidence: 99%

Sirtuins as Potential Therapeutic Targets for Mitigating Neuroinflammation Associated With Alzheimer’s Disease

Fernando

Wijayasinghe

2021

Front. Cell. Neurosci.

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Alzheimer’s disease (AD) is the most common neurodegenerative disorder, which is associated with memory deficit and global cognitive decline. Age is the greatest risk factor for AD and, in recent years, it is becoming increasingly appreciated that aging-related neuroinflammation plays a key role in the pathogenesis of AD. The presence of β-amyloid plaques and neurofibrillary tangles are the primary pathological hallmarks of AD; defects which can then activate a cascade of molecular inflammatory pathways in glial cells. Microglia, the resident macrophages in the central nervous system (CNS), are the major triggers of inflammation; a response which is typically intended to prevent further damage to the CNS. However, persistent microglial activation (i.e., neuroinflammation) is toxic to both neurons and glia, which then leads to neurodegeneration. Growing evidence supports a central role for sirtuins in the regulation of neuroinflammation. Sirtuins are NAD+-dependent protein deacetylases that modulate a number of cellular processes associated with inflammation. This review examines the latest findings regarding AD-associated neuroinflammation, mainly focusing on the connections among the microglial molecular pathways of inflammation. Furthermore, we highlight the biology of sirtuins, and their role in neuroinflammation. Suppression of microglial activity through modulation of the sirtuin activity has now become a key area of research, where progress in therapeutic interventions may slow the progression of Alzheimer’s disease.

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Replicative senescence dictates the emergence of disease-associated microglia and contributes to Aβ pathology

Cited by 154 publications

References 56 publications

Microglial responses to CSF1 overexpression do not promote the expansion of other glial lineages

Microglial responses to CSF1 overexpression do not promote the expansion of other glial lineages

Insights Into the Role of CSF1R in the Central Nervous System and Neurological Disorders

Sirtuins as Potential Therapeutic Targets for Mitigating Neuroinflammation Associated With Alzheimer’s Disease

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