CSF1R inhibitor PLX5622 and environmental enrichment additively improve metabolic outcomes in middle-aged female mice

Ali, Seemaab; Mansour, Anthony G.; Huang, Wei; Queen, Nicholas J.; Mo, Xiaokui; Anderson, Jacqueline M.; Hassan, Quais N.; Patel, Ripal; Wilkins, Ryan K.; Caligiuri, Michael A.; Cao, Lei

doi:10.18632/aging.102724

Cited by 25 publications

(21 citation statements)

References 52 publications

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“…Most of the research groups used a molecule that inhibits CSF1R signalization, namely PLX5622. Interestingly, by impeding mCSF signal, they observed a massive microglial depletion, suggesting a central role of mCSF/CSF1R axis in microglia survival [43,[45][46][47][48][49]. Lately, we have demonstrated the effect of CSF1R ablation on microglia is depending on the context.…”

Section: Discussionmentioning

confidence: 84%

Conditional genetic deletion of CSF1 receptor in microglia ameliorates the physiopathology of Alzheimer’s disease

et al. 2021

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Background Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and the most common form of dementia in the world. Microglia are the innate immune cells of CNS; their proliferation, activation, and survival in pathologic and healthy brain have previously been shown to be highly dependent on CSF1R. Methods Here, we investigate the impact of such receptor on AD etiology and microglia. We deleted CSF1R using Cre/Lox system; the knockout (KO) is restricted to microglia in the APP/PS1 mouse model. We induced the knockout at 3 months old, before plaque formation, and evaluated both 6- and 8-month-old groups of mice. Results Our findings demonstrated that CSF1R KO did not impair microglial survival and proliferation at 6 and 8 months of age in APP cKO compared to their littermate-control groups APPSwe/PS1. We have also shown that cognitive decline is delayed in CSF1R-deleted mice. Ameliorations of AD etiology are associated with a decrease in plaque volume in the cortex and hippocampus area. A compensating system seems to take place following the knockout, since TREM2/β-Catenin and IL-34 expression are significantly increased. Such a compensatory mechanism may promote microglial survival and phagocytosis of Aβ in the brain. Conclusions Our results provide new insights on the role of CSF1R in microglia and how it interacts with the TREM2/β-Catenin and IL-34 system to clear Aβ and ameliorates the physiopathology of AD.

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Section: Discussionmentioning

confidence: 84%

Conditional genetic deletion of CSF1 receptor in microglia ameliorates the physiopathology of Alzheimer’s disease

et al. 2021

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“…Most of research groups used a molecule which inhibits CSF1R signalization, namely PLX5622. Interestingly, by impeding mCSF signal they observed a massive microglial depletion, suggesting a central role of mCSF/CSF1R axis in microglia survival (36,(38)(39)(40)(41)(42). Lately, we have demonstrated the effect of CSF1R ablation on microglia is depending on the context.…”

Section: Discussionmentioning

confidence: 85%

Conditional genetic deletion of CSF1 receptor in microglia ameliorates the physiopathology of Alzheimer’s disease

Pons

Lévesque²,

Plande

et al. 2020

Preprint

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BackgroundAlzheimer’s disease (AD) is a progressive neurodegenerative disorder and the most common form of dementia in the world. Microglia are the innate immune cells of CNS, their proliferation, activation and survival in pathologic and healthy brain have previously been shown to be highly dependent on CSF1R.MethodsHere we investigate the impact of such receptor on AD etiology and microglia. We deleted CSF1R using Cre/Lox system, the knock-out (KO) is restricted to microglia in the APP/PS1 mouse model. We induced the knock-out at 3-month-old, before plaque formation and evaluated both 6 and 8-month-old groups of mice.ResultsOur findings demonstrated that CSF1R KO did not impair microglial survival and proliferation at 6 and 8 months of age in APP cKO compared to their littermate controls groups APPSwe/PS1. We have also shown that cognitive decline is delayed in CSF1R-deleted mice. Ameliorations of AD etiology is associated with a decrease in plaque volume in cortex and hippocampus area. A compensating system seems to take place following the knock-out, since TREM2/β-Catenin and IL-34 expression are significantly increased. Such a compensatory mechanism may promote microglial survival and phagocytosis of Aβ in the brain.ConclusionsOur results provide new insights on the role of CSF1R in microglia and how it interacts with the TREM2/β-Catenin and IL-34 system to clear Aβ and ameliorates the physiopathology of AD.

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“…Fortunately, Csf1r is also expressed by microglia from the ARC and ME [ 108 ] ( Figure 4 ). CSF1R inhibition through a pharmacologic inhibitor (PLX5622) can improve metabolic outcomes in middle-aged female mice [ 155 ]. Thus, investigating the role of Csfr1+ microglial cells in the hypothalamic inflammation, through this Csf1r-FIRE Δ/Δ mouse model, could also provide new, important information regarding this subtype of microglia.…”

Section: Advances In Experimental Manipulation Of Microgliamentioning

confidence: 99%

Hypothalamic Microglial Heterogeneity and Signature under High Fat Diet–Induced Inflammation

Mendes

Jara

Zanesco

et al. 2021

IJMS

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Under high-fat feeding, the hypothalamus atypically undergoes pro-inflammatory signaling activation. Recent data from transcriptomic analysis of microglia from rodents and humans has allowed the identification of several microglial subpopulations throughout the brain. Numerous studies have clarified the roles of these cells in hypothalamic inflammation, but how each microglial subset plays its functions upon inflammatory stimuli remains unexplored. Fortunately, these data unveiling microglial heterogeneity have triggered the development of novel experimental models for studying the roles and characteristics of each microglial subtype. In this review, we explore microglial heterogeneity in the hypothalamus and their crosstalk with astrocytes under high fat diet–induced inflammation. We present novel currently available ex vivo and in vivo experimental models that can be useful when designing a new research project in this field of study. Last, we examine the transcriptomic data already published to identify how the hypothalamic microglial signature changes upon short-term and prolonged high-fat feeding.

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CSF1R inhibitor PLX5622 and environmental enrichment additively improve metabolic outcomes in middle-aged female mice

Abstract: Recently, attention has been focused on adipose tissue as an important player in the aging processes. Adipose tissue comprises a dynamic and interconnected endocrine www.aging-us.com

Cited by 25 publications

References 52 publications

Conditional genetic deletion of CSF1 receptor in microglia ameliorates the physiopathology of Alzheimer’s disease

Conditional genetic deletion of CSF1 receptor in microglia ameliorates the physiopathology of Alzheimer’s disease

Conditional genetic deletion of CSF1 receptor in microglia ameliorates the physiopathology of Alzheimer’s disease

Hypothalamic Microglial Heterogeneity and Signature under High Fat Diet–Induced Inflammation

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