Abstract
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 Aβ 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.
Highlights
1234567890();,: INTRODUCTION Alzheimer’s disease (AD) is an irreversible neurodegenerative pathology commonly characterized by overt buildup of amyloid β-peptide (Aβ) and neurofibrillary tangles, which results in memory loss, cognitive impairment, and shortened lifespan.[1]
Our findings suggest that AD patients exhibit cardiac dysfunction in association with low levels of circulating melatonin, Beclin[1], and ALDH2 activity
Exactly how AD pathology leads to low-circulating melatonin levels is beyond the scope of our present study, but interrupted circadian cycle
Summary
Alzheimer’s disease (AD) is an irreversible neurodegenerative pathology commonly characterized by overt buildup of amyloid β-peptide (Aβ) and neurofibrillary tangles, which results in memory loss, cognitive impairment, and shortened lifespan.[1] AD etiology is predominantly idiopathic, an autosomal dominant disorder elicited by mutant β-amyloid precursor protein (APP), presenilin 1 (PS1), or presenilin 2 (PS2) is believed to contribute to familial AD.[2]. Earlier findings from our own laboratory and others demonstrated pronounced cardiac anomalies in this murine model of AD.[11,12,13]
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