ALDH2 contributes to melatonin induced protection against APP/PS1 mutation prompted cardiac anomalies through cGAS STING TBK1 mediated regulation of mitophagy
Ample clinical evidence suggests a high incidence of cardiovascular events in Alzheimer's disease (AD) although neither precise etiology nor effective treatment is available. This study was designed to evaluate cardiac function in AD patients and APP/PS1 mutant mice, along with circulating levels of melatonin, mitochondrial aldehyde dehydrogenase (ALDH2) and autophagy. AD patients and APP/PS1 mice displayed cognitive and myocardial deficits, low levels of circulating melatonin, ALDH2 activity, and autophagy, ultrastructural, geometric (cardiac atrophy and interstitial fibrosis) and functional (reduced fractional shortening and cardiomyocyte contraction) anomalies, mitochondrial injury, cytosolic mtDNA buildup, apoptosis, and suppressed autophagy and mitophagy. APP/PS1 mutation downregulated cyclic GMP AMP synthase (cGAS) and stimulator of interferon genes (STING) levels and TBK1 phosphorylation, while promoting Ab accumulation. Treatment with melatonin overtly ameliorated unfavorable APP/PS1 induced changes in cardiac geometry and function, apoptosis, mitochondrial integrity, cytosolic mtDNA accumulation (using both immunocytochemistry and qPCR) mitophagy, and cGAS STING TBK1 signaling, although these benefits were absent in APP/PS1/ALDH2 mice. In vitro evidence indicated that melatonin attenuated APP/PS1 induced suppression of mitophagy and cardiomyocyte function, and the effect was negated by the nonselective melatonin receptor blocker luzindole, inhibitors or RNA interference of cGAS, STING, TBK1, and autophagy. Our data collectively established a correlation among cardiac dysfunction, low levels of melatonin, ALDH2 activity, and autophagy in AD patients, with compelling support in APP/PS1 mice, in which melatonin rescued myopathic changes by promoting cGAS STING TBK1 signaling and mitophagy via an ALDH2 dependent mechanism.
Signal Transduction and Targeted Therapy