Abstract
Neurogenesis is altered in neurodegenerative disorders, partly regulated by inflammatory factors. We have investigated whether microglia, the innate immune brain cells, regulate hippocampal neurogenesis in neurodegeneration. Using the ME7 model of prion disease we applied gain- or loss-of CSF1R function, as means to stimulate or inhibit microglial proliferation, respectively, to dissect the contribution of these cells to neurogenesis. We found that increased hippocampal neurogenesis correlates with the expansion of the microglia population. The selective inhibition of microglial proliferation caused a reduction in neurogenesis and a restoration of normal neuronal differentiation, supporting a pro-neurogenic role for microglia. Using a gene screening strategy, we identified TGFβ as a molecule controlling the microglial pro-neurogenic response in chronic neurodegeneration, supported by loss-of-function mechanistic experiments.By the selective targeting of microglial proliferation we have been able to uncover a pro-neurogenic role for microglia in chronic neurodegeneration, suggesting promising therapeutic targets to normalise the neurogenic niche during neurodegeneration.
Highlights
Mammalian adult hippocampal neurogenesis is an active process in the healthy brain and is modulated in response to brain injury and neurodegeneration (Parent 2003)
We have demonstrated that some factors derived from microglia contribute to the aberrant increase in neurogenesis, and play a role in the abnormal development and differentiation of newborn neurons as evidenced by the restoration of a normal differentiation program when microglial proliferation was inhibited
Previous studies are in line with our findings as they show the important contribution of microglia for the maintenance and support of hippocampal neurogenesis in the steady state and during pathological events(Butovsky et al 2006; Ekdahl et al 2009; Ziv et al 2006)
Summary
Mammalian adult hippocampal neurogenesis is an active process in the healthy brain and is modulated in response to brain injury and neurodegeneration (Parent 2003). There is a clear need for a better understanding of neurogenesis during chronic neurodegeneration, arising from experimental models that recapitulate the human pathophysiology In this line, models of prion disease have been used to mimic chronic neurodegeneration, as they are reproducible and recapitulate phenotypes present in several neurodegenerative diseases, such as microglial activation, misfolded protein deposition and neurodegeneration, making them an excellent model to study some of the mechanisms involved in neurodegeneration and neurogenesis (Gomez-Nicola and Perry 2014a; GomezNicola et al 2014d). The neurogenic impairment seen after LPS injection can be rescued by treatment with minocycline or anti-inflammatory drugs, suggesting a microglia-dependent mechanism (Ekdahl et al 2003; Monje et al 2003) Together, these studies suggest a key role for microglia in regulating neurogenesis in disease. We hypothesise that the control of microglial numbers, by means of up- or down-regulating their proliferation (gain- or loss-of-activity of CSF1R), will help dissecting the contribution of these cells to hippocampal neurogenesis in prion disease, and further identify any molecular determinants of this response. Our results link neuroinflammation and neurogenesis during chronic neurodegeneration, and open new avenues to explore the therapeutic value of immunomodulatory strategies to control the self-repairing potential of the brain
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