Age-related Dysregulation of Autophagy Contributes to Microglial Dysfunction and Chronic Neurobehavioral Deficits After Traumatic Brain Injury

Background: Elderly patients with traumatic brain injury (TBI) have greater mortality and poorer outcomes than younger individuals. Given the critical role for autophagy in promoting the cellular degradation of damaged organelles and the negative impact of aging on this protective mechanism, we hypothesized that treatment with an autophagic inducer such as trehalose may be a promising therapeutic strategy for TBI aged animals. Methods: Controlled cortical impact was used to induce moderate TBI in male C57BL/6 mice. Young (10 weeks) or old (18 months) animals were evaluated behaviorally for 12 weeks after injury. Autophagy, inflammation, and neurodegeneration were examined using NanoString analysis, flow cytometry, and immunohistochemistry. Trehalose or sucrose as a control were administered in drinking water beginning day1 post-injury for 8 weeks. Results: Aged mice had a higher mortality rate than young mice at 12 weeks post-injury. At 12 weeks, aged mice showed greater cognitive deficits and depression than younger animals. There were also larger lesion volumes and increased microglial activation in aged TBI mice at 16 weeks post-injury. NanoString analysis identified several age- and TBI-specific genes changes that were differentially expressed in the chronically injured brain, including those involved with the complement, phagocytosis, and autophagy pathways. Flow cytometry demonstrated temporal dysregulation of phagocytosis and autophagy in microglia from injured mice that were exacerbated with age and accompanied by an increased inflammation and lymphocyte infiltration. Old TBI mice treated with trehalose exhibited either more delayed deficits or enhanced recovery in cognitive and motor tasks. In addition, Trehalose treatment modified expression of autophagy markers and attenuated the microglial response to TBI. Conclusions: Our data indicate that microglia undergo chronic changes in autophagic regulation with both normal aging and TBI that are associated with poorer functional outcome. Enhancing autophagy may therefore be a promising clinical therapeutic strategy for TBI, especially in older patients.