Exercise‐Associated Modulation of Neuroinflammation in Alzheimer's Disease

Background Exercise promotes powerful systemic and central nervous system anti‐inflammatory effects, even during aging. Exercise also limits neuroinflammation in models of Alzheimer's disease (AD), thereby inhibiting disease progression and promoting other well‐documented neuroprotective effects such as supporting neuronal plasticity, stimulating adult neurogenesis, and enhancing cognitive function. However, exercise is not always accessible to aging populations that are most at risk for developing AD. Method We have recently derived transgenic mice that moderately overexpress Transcription Factor EB (TFEB), a lysosome biogenesis promoter, in skeletal muscle (cTFEB;HSA‐Cre mice) which resulted in enhanced muscle proteostasis, similar to what is observed with long‐term exercise regimes. These mice were then bred with 5xFAD AD‐model mice and evaluated for CNS hallmarks of AD, hippocampal neuroinflammation, and CNS amyloid beta plaque accumulation, at two time points (age=4 months, 8 months). Result cTFEB;HSA‐Cre;5xFAD mice were observed to have similar inflammatory expression patterns as plaque‐free controls compared to 5xFAD mice. Preliminary analysis also indicates lower amyloid beta plaque load in cTFEB;HSA‐Cre;5xFAD mice. We are currently performing Nanostring analysis with the AD nCounter panel and neuroinflammation nCounter panel to identify transcriptional changes in neuroinflammatory signaling and ameliorating mechanisms associated with skeletal muscle TFEB overexpression. Conclusion We have identified an exercise‐regulated pathway through which AD‐associated neuroinflammation can potentially be ameliorated and plaque burden modulated. These results support the discovery of an exciting therapeutic intervention against AD progression that eliminates the need for strenuous exercise. We are currently identifying essential exercise‐associated cytokines that can reduce AD‐associated neuroinflammation and prevent disease progression, as well as establish a therapeutic exercise mimetic to combat amyloid beta‐associated neurodegeneration.