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

Abstract

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.

A CRISPRi/a platform in iPSC-derived microglia uncovers regulators of disease states

“…Following CSF1R inhibition, we found an enrichment of microglia states with elevated markers of inflammatory chemokines and proliferation and interestingly, in concordance with our findings in iTF-Microglia here, an upregulation of cell surface receptor CD74 63 . Others have reported compensatory upregulation of TREM2/ β -catenin and IL-34 in microglia following conditional CSF1R KO 77 ; however, we did not find consistent upregulation of these factors in our iTF-microglia (Supplementary Table 9). Based on our new finding that CSF1R inhibition at low doses that are nontoxic to most microglia selectively depletes the SPP1+ population in iTF-Microglia, low-dose CSF1R inhibition might also give us a tool to study the SPP1+ population in mouse disease models.…”

Single-cell-led drug repurposing for Alzheimer’s disease

“…Interestingly, some of these signaling axes have been previously investigated for the identification of new AD treatments in preclinical studies. For example, recent studies investigated the potential of targeting the CSF1R/IL34 axis to reduce the microglial activation and neuroinflammation present in AD [42][43][44] . The ligand-receptor pair CX3CL1/CX3CR1 in AD was also investigated for its role in AD [45][46][47] .…”

Decreased Levels of Serum IL-34 Associated with Cognitive Impairment in Vascular Dementia

“…In addition, West Nile virus infection can cause cognitive impairment, and IL-34 knockout mice can reduce the synaptic loss caused by this virus infection, suggesting that IL-34 may participate in the course of cognitive impairment [33]. Canadian researchers initially revealed the mechanism by which IL-34 is involved in the pathogenesis of AD [34], but its relationship with VaD has not been reported yet.…”