Characterization of BACE1/BACE1-AS/β-amyloid axis in cardiovascular risk conditions: exploring its pathophysiological miRNAs connection

Beta-Secretase 1 antisense (BACE1-AS) long non-coding RNA is an antisense transcript of BACE1, the key-rate limiting enzyme for the production of β-amyloid (Aβ), which is involved in the pathogenesis of Alzheimer's disease (AD). It is known that BACE1-AS stabilizes the BACE1 mRNA both directly and preventing its degradation through the sequestration of BACE1-targeting miRNAs, leading to increased levels of Aβ production [1]. Given the growing evidence of a correlation between cardiovascular and neurodegenerative diseases, several research groups have focused on investigating their connection. In 2017, Greco et al. observed that BACE1 and BACE1-AS levels increased in the myocardium of ischemic heart failure (HF) patients compared to healthy controls [2]. Given the severity of the disease and the absence of effective therapies, identifying the molecular mechanisms underpinning epigenetic and transcriptomic regulation in ischemic HF is a clear unmet need. This project explores the clinical relevance of BACE1-AS and BACE1 as potential biomarkers in ischemic HF. To this aim, their expression and regulation have been assayed in the peripheral blood mononuclear cells (PBMCs) of subjects affected by the disease. Their levels were correlated to clinical data obtained from patients to deepen the connection between BACE1/BACE1-AS and HF- related parameters. In the study, amyloid levels were also assayed in the plasma of HF patients. Moreover, miRNAs were analyzed, as they are known to regulate several pathophysiological processes. In addition, epigenetic effects induced by BACE1-AS have been examined in AC16 cardiomyocytes, aiming to evaluate BACE1-AS independent function from BACE1 regulation. The study also provided the possibility to evaluate new targets potentially connected with the BACE1/BACE1-AS axis and HF. Understanding the intricate roles of BACE1-AS and BACE1, along with their regulatory mechanisms and associations with clinical parameters in ischemic heart failure, could significantly enhance early diagnosis and pave the way for improved therapeutic strategies. This more profound insight into their molecular and epigenetic interactions has the potential to address critical unmet needs in managing this severe condition.