Voluntary running shows limited neuroprotection in mice

In 5xFAD mice, prolonged exercise failed to generate broad neuroprotective benefits despite engaging peripheral metabolism, according to a preprint on bioRxiv. Researchers gave male and female mice continuous access to either a free or locked running wheel for approximately 16 weeks, beginning at six and three months of age, respectively. Running triggered expected adaptations in peripheral fat, reducing inguinal white adipose tissue mass in females and increasing thermogenic gene markers in both sexes. However, hippocampal molecular changes were modest. Bulk RNA sequencing identified only four differentially expressed genes in males and none in females. While pathway analyses revealed shifts in synaptic, mitochondrial, and immune programs, these did not translate into increased synapse density or reduced amyloid plaque burden. Exercise also failed to improve spatial learning, memory, or species-typical nesting behavior.