Age-Related Alterations in the Expression of Mesencephalic Astrocyte-derived Neurotrophic Factor in the Brain and Their Impact on Neurobehavioral Functions

Mesencephalic astrocyte-derived neurotrophic factor (MANF) is a neurotrophic protein localized in the endoplasmic reticulum (ER) and pivotally involved in maintaining ER homeostasis. MANF plays an important role in mitigating neurodegenerative processes. Aging, the primary risk factor for neurodegenerative diseases (NDDs), is associated with significant alterations in ER function. The ER, central to protein synthesis, folding, degradation and secretion (proteostasis), experiences considerable stress in NDDs, which activates the unfolded protein response (UPR). We hypothesized that MANF and UPR is crucial for maintaining proteostasis during aging, but their efficacy declines with age, therefore increasing vulnerability to NDDs. We measured MANF levels in the brain and plasma of 1-, 4-, 11-, and 22-month-old male and female mice. A progressive decline of MANF levels was observed, with the lowest levels detected in 22 months. Reduced MANF expression was found in aged mice across several brain areas, including the cerebral cortex, olfactory bulb, thalamus, hypothalamus, hippocampus, and cerebellum. There was a sex difference in MANF levels in aged mice. Aging also altered the expression of UPR and MANF interacting proteins. Using cerebellar Purkinje cell (PC)-specific MANF deficient mice, we showed that MANF deficiency impaired motor coordination in female, but not male mice. MANF deficiency weakened spatial learning and memory in both male and female mice. Male MANF deficient mice displayed increased sociability, whereas female mice exhibit social withdrawal. Taken together, MANF expression in the brain declined with age and MANF deficiency impacted neurobehaviors in the aging animal in a sex-specific manner.