Alteration in mitochondrial dynamics promotes the proinflammatory response of microglia and is involved in cerebellar dysfunction of young and aged mice following LPS exposure

Abstract

Cerebellar dysfunction is implicated in impaired motor coordination and balance, thus disturbing the dynamics of sensorimotor integration. Neuroinflammation and aging could be prominent contributors to cerebellar aberration. Additionally, changes in mitochondrial dynamics may precede microglia activation in several chronic neurodegenerative diseases; however, the underlying mechanism remains largely unknown. Here using LPS (1 mg/kg i.p. for four consecutive days) stimulation in both young (3 months old) and aged (12 months old) mice, followed by molecular analysis on the 21st day, we have explored the correlation between aging and mitochondrial dynamic alteration in the backdrop of chronic neuroinflammation. Following LPS stimulation, we observed microglia activation and subsequent elevation in proinflammatory cytokines (M1; TNF-α, IFN-γ) with NLRP3 activation and a concomitant reduction in the expression of anti-inflammatory markers (M2; YM1, TGF-β1) in the cerebellar tissue of aged mice compared with the young LPS and aged controls. Remarkably, senescence (p21, p27, p53) and epigenetic (HDAC2) markers were found upregulated in the cerebellum tissue of the aged LPS group, suggesting their crucial role in LPS-induced cerebellar deficit. Further, we demonstrated alteration in the antagonistic forces of mitochondrial fusion and fission with increased expression of the mitochondrial fission-related gene [FIS1] and decreased fusion-related genes [MFN1 and MFN2]. We noted increased mtDNA copy number, microglia activation, and inflammatory response of IL1-β and IFN-γ post-chronic neuroinflammation in aged LPS group. Our results suggest that the crosstalk between mitochondrial dynamics and altered microglial activation paradigm in chronic neuroinflammatory conditions may be the key to understanding the cerebellar molecular mechanism.