Inhibition of α‐Synuclein Accumulation Improves Neuronal Apoptosis and Delayed Postoperative Cognitive Recovery in Aged Mice

Delayed neurocognitive recovery (dNCR) is a major complication after anesthesia and surgery in older adults. Alpha-synuclein ( α -syn; encoded by the gene, SNCA ) has recently been shown to play an important role in hippocampus-dependent working memory. Aggregated forms of α -syn are associated with multiple neurotoxic mechanisms, such as mitochondrial dysfunction and cell death. In this study, we found that blocking α -syn improved both mitochondrial function and mitochondria-dependent neuronal apoptosis in a mouse model of dNCR. Various forms of α -syn (including total α -syn, phosphorylated-Ser129- α -syn, and oligomers) were upregulated in hippocampal tissue and extracted mitochondria after surgical challenge. Clenbuterol is a novel transcription modulator of Scna . Clenbuterol significantly attenuated surgery-induced progressive accumulation of various toxic α -syn forms in the hippocampus, as well as mitochondrial damage and memory deficits in aged mice following surgery. We also observed excessive mitochondrial α -syn accumulation and increased mitochondria-mediated apoptosis in vitro using nerve growth factor-differentiated PC12 cells and primary hippocampal neurons exposed to lipopolysaccharide. To further validate the neuroprotective effect of α -syn inhibition, we used a lentiviral Snca -shRNA (Lv-shSnca) to knockdown Snca . Of note, Lv-shSnca transfection significantly inhibited neuronal apoptosis mediated by the mitochondrial apoptosis pathway in neurons exposed to lipopolysaccharide. This α -syn inhibition improved the disruption to mitochondrial morphology and function, as well as decreased levels of apoptosis. Our results suggest that targeting pathological α -syn may achieve neuroprotection through regulation of mitochondrial homeostasis and suppression of apoptosis in the aged hippocampus, further strengthening the therapeutic potential of targeting α -syn for dNCR.