CSF1R inhibitor JNJ-40346527 attenuates microglial proliferation and neurodegeneration in P301S mice

Abstract

Microglia have been implicated in amyloid beta-induced neuropathology, but their role in tau-induced neurodegeneration remains unclear. Mancuso et al. report that blockade of microglial proliferation by CSF1R inhibitor JNJ-40346527 modifies brain inflammation and ameliorates disease progression in P301S tauopathy mice. CSF1R inhibition may have therapeutic potential in tau-mediated neurodegenerative diseases.

Inhibition of IL34 unveils tissue-selectivity and is sufficient to reduce microglial proliferation in chronic neurodegeneration

“…This high abundance of IL-34 in the brain emphasizes the difficulty in efficiently targeting this cytokine with neutralizing antibodies Similarly, peripheral administration of CSF1R blocking antibodies did not lead to a reduction in microglia in cortex, dentate gyrus and CA1. The fact that blocking CSF1R using small molecule inhibitors resulted in pronounced depletion of microglia in several mouse models 5,7,8,10 , further indicates that the strategy applied in this study using blocking antibodies is not favourable. Lin et al and Easley-Neal et al, provide first proof that manipulation of IL-34 can be used to modify the microglia population in the gray matter of most brain regions 32 and that this approach might be relevant in the context of inflammatory diseases and cancer 31 .…”

“…It was demonstrated previously that CSF1R inhibition using tyrosine kinase inhibitors can be used as a strategy to decrease microglia proliferation in neurodegenerative disease models, which led to beneficial effects such as reduced neuronal loss and behavioural deficits in mouse models of prion disease 5 , tau pathology 10 and Aβ pathology 8 , 7 . Long-term CSF1R inhibition could potentially increase risk of infections and lead to disturbance of tissue homeostasis due to the reduction of CSF1R-dependent macrophage populations in multiple organs.…”

“…Similarly, a prolonged inhibition of the tyrosine kinase activity of CSF1R blocks microglial proliferation and prevents synaptic degeneration, ameliorating disease progression, in the APP/PS1 model 6 , the 3xTg model 7 and the 5xFAD model 8,9 of AD-like pathology. More recently, our group has validated this disease-modifying mechanism in the P301S mouse of tauopathy, demonstrating that inhibition of CSF1R is effective in repolarising microglia to a homeostatic phenotype, preventing neuronal degeneration 10 . In recent years, the therapeutic potential of blocking antibodies and small molecule CSF1R kinase inhibitors has been demonstrated in inflammatory diseases, neurological disorders, bone diseases and cancer, with some candidates currently in clinical phase testing [11][12][13] .…”

Bayesian integrative analysis of epigenomic and transcriptomic data identifies Alzheimer's disease candidate genes and networks

“…A few studies of AD focused on the corresponding receptor CSF1R as a potential therapeutic target. Microglia cells depend on CSF1R signaling [111,112] and treatment of AD mice with CSF1R inhibitors results in reduced microglia activation and improved memory function [70,113], but little is known about the cells that contribute to CSF1R triggering in AD. Using snRNA-seq data, we showed that the upregulation of CSF1 observed at the tissue level is primarily caused by astrocytes in human AD brains.…”

Microglia/macrophage diversities in central nervous system physiology and pathology

“…Some studies documented the destructive role of microglia/macrophages in brain pathologies as highly activated microglia release a plethora of neurotoxic factors, including inflammatory cytokines, chemokines, and free radicals. In support of this view, microglia depletion has been reported to result in neuroprotection in experimental models of hemorrhagic stroke, chronic cerebral hypoperfusion, traumatic brain injury (TBI), and Alzheimer's disease (AD) . In contrast, quite a few studies documented that the removal of microglia enhanced neuroinflammation and thus exacerbated the neurological deficits after brain injuries or neurodegenerations, suggesting beneficial roles of microglia in the presence of CNS pathologies .…”