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

Abstract

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