Alda-1 Alleviates the Cognitive Deficits in D-galactose-induced Aging Mice by Regulating Oxidative Stress, Neuroinflammation, and Mitochondrial Biogenesis

Abstract Although mitochondrial aldehyde dehydrogenase 2 (ALDH2) is involved in aging and age-related neurodegenerative diseases, the impact of ALDH2 on age-related cognitive deficits and its underlying mechanisms have not been fully elucidated. This study aimed to explore the effects of ALDH2 on cognitive deficits in D-galactose-induced aging mice and illustrate the potential molecular mechanisms. We treated D-galactose-induced aging mice with Alda-1 (a potent agonist of ALDH2) for eight weeks and observed the alterations in behavior, levels of oxidative stress and neuroinflammation, mitochondrial function, and expression of mitochondrial biogenesis-related genes. The results revealed that Alda-1 alleviated neuropathological changes in the hippocampus and ameliorated cognitive deficits in D-galactose-induced aging mice. Administration of Alda-1 further reduced the levels of 4-HNE, MDA, 3-NT, IL-6, TNF-α, and IL-1β; enhanced Mn-SOD and CAT activities; increased GSH and ATP levels and mitochondrial content; and upregulated PGC-1α/NRF-1/TFAM expression in the hippocampus of D-galactose-induced aging mice. Moreover, in D-galactose-treated HT22 cells, we found that the SIRT1 inhibitor EX527 reversed the Alda-1-induced upregulation of PGC-1α, suggesting that the Alda-1-induced upregulation of PGC-1α is associated with SIRT1 signaling. Collectively, Alda-1 ameliorated cognitive deficits in D-galactose-induced aging mice by reducing neuroinflammation, enhancing antioxidative capability, promoting mitochondrial biogenesis, and modulating the SIRT1/PGC-1α signaling pathway.