Sesaminol Ameliorates Age-Related Cognitive Decline and Neuroinflammation by Modulating Microglial Polarization and Enhancing Aβ Phagocytosis in Mice

Microglia are pivotal regulators of neuroimmune homeostasis in the central nervous system, and their dysregulation is linked to neurodegeneration and brain aging. Among the principal sesame-seed lignans, sesamin has demonstrated robust neuroprotective effects via antioxidant and anti-inflammatory pathways, whereas the neural actions and underlying mechanisms of sesaminol remain undefined. Here, we compared sesaminol with sesamin regarding cognition, neuroinflammation, and microglial polarization in middle-aged mice, and assessed the effects of sesaminol in LPS-challenged mice. In middle-aged mice, sesaminol restored spatial and recognition memory and amplified hippocampal neurotrophic signaling, while sesamin showed only modest benefits. Sesaminol also reversed LPS-induced cognitive deficits in mice. Moreover, sesaminol suppressed oxidative stress and neuroinflammation, and shifted the microglia toward an M2-dominant phenotype, probably in a HIF-1α-dependent manner. Furthermore, sesaminol accelerated Aβ40/42 clearance by upregulating lysosomal functions. Thus, sesaminol restores microglial homeostasis and Aβ clearance to counter chronic and acute cognitive decline and might be one potential antiaging agent.