Aß exacerbates α-synuclein-induced neurotoxicity through impaired insulin signaling in α-synuclein-overexpressed human SK-N-MC neuronal cells.

AIM: α-Synuclein (αSyn) is known as a small soluble protein abundantly expressed in neuronal cells. Although its physiological role is still unclear, the aggregation of αSyn has been recognized as responsible for some neurodegenerative disorders such as dementia with Lewy bodies (DLB). In most cases, intracellular abnormal aggregates are caused by protein-coding mutations that alter primary structure and therefore increase propensity toward aggregation. However, no pathogenic alterations or polymorphisms in αSyn are found in DLB patients so far, suggesting genetic mutations may not play a major role in DLB pathogenesis. In contrast, emerging evidence reveals that amyloid ß (Aß) may contribute to aggregate formation and exacerbate neurotoxicity of αSyn. However, the underlying mechanism of action has remained unclear. METHODS: To investigate molecular pathways involved in Aß-mediated αSyn pathology, we established an in vitro model for inducible αSyn overexpression in SK-N-MC human neuronal cells. RESULTS: Our results demonstrated that Aß treatment in αSyn-overexpressed neuronal cells significantly increases αSyn intracellular aggregation and cytotoxicity. Moreover, Aß also caused AMP-activated protein kinase (AMPK) inhibition and impaired insulin sensitivity, which leads to significant downregulation of nuclear factor erythroid 2-related factor 2 (NRF2)/heme oxygenase 1 (HO-1) antioxidant signaling to elicit αSyn aggregation. CONCLUSIONS: This raised the possibility that insulin resistance could be one of the causative factors of αSyn toxicity, and the strategies for insulin sensitization may have therapeutic potential for synucleinopathies including DLB.

Amyloid-ß suppresses AMP-activated protein kinase (AMPK) signaling and contributes to α-synuclein-induced cytotoxicity.

Dementia with Lewy bodies (DLB) is a neurodegenerative disorder caused by abnormal accumulation of Lewy bodies, which are intracellular deposits composed primarily of aggregated α-synuclein (αSyn). Although αSyn has been strongly implicated to induce neurotoxicity, overexpression of wild-type αSyn is shown to be insufficient to trigger formation of protein aggregates by itself. Therefore, investigating the possible mechanism underlying αSyn aggregation is essential to understand the pathogenesis of DLB. Previous studies have demonstrated that amyloid ß (Aß), the primary cause of Alzheimer's disease (AD), may promote the formation of αSyn inclusion bodies. However, it remains unclear how Aß contributes to the deposition and neurotoxicity of αSyn. In the present study, we investigated the cytotoxic effects of Aß in αSyn-overexpressed neuronal cells. Our results showed that Aß inhibits autophagy and enhances αSyn aggregation in αSyn-overexpressed cells. Moreover, Aß also reduced sirtuin 1 (Sirt1) and its downstream signaling, resulting in increased intracellular ROS accumulation and mitochondrial dysfunction. Our in vitro and in vivo studies support that Aß-inhibition of AMP-activated protein kinase (AMPK) signaling is involved in the neurotoxic effects of αSyn. Taken together, our findings suggest that Aß plays a synergistic role in αSyn aggregation and cytotoxicity, which may provide a novel understanding for exploring the underlying molecular mechanism of DLB.