Understanding the Cardiac Benefits of Exercise at the Cellular and Molecular Level

Project Summary/Abstract Alzheimer’s disease (AD) is the most common form of dementia and its prevalence is increasing as the world population ages. Interestingly, AD shares many risk factors with heart failure (HF) and the two diseases are often comorbid. Although AD and HF are both incurable and the efficacy of existing therapeutics

is limited, in both cases exercise is one of the few interventions known to have protective effects. Our long- term, over-arching goals are to understand these concordant patterns in vulnerability to HF and AD, learn whether common pathways are involved, and determine if they can be exploited for therapeutic benefit. In

preliminary studies, we identified a long noncoding (lnc) RNA, lncExACT1, that is downregulated in exercised hearts and upregulated in both human and experimental HF. In functional studies, lncExACT1 overexpression was sufficient to cause cardiac dysfunction while its inhibition with modified antisense

oligonucleotides protected against HF, raising the possibility that pharmacological lncExACT1 inhibitors could have valuable therapeutic applications. Interestingly, our preliminary data also revealed lncExACT1 is expressed in the brain at even higher levels than in the heart and suggested that brain lncExACT1 is also

dynamically regulated with exercise and cardiovascular disease. Furthermore, in an AD mouse model (APP/PS1), lncExACT1 expression was increased in the hippocampus, a brain region that is particularly vulnerable to atrophy in AD, and a similar increase was detected in multiple neocortical brain regions from

AD patients. The goal of this supplement is to further evaluate the role of lncExACT1 in AD. We hypothesize that, mirroring its role in the heart during HF, brain lncExACT1 contributes to the development and progression of AD, with exercise preventing or slowing the development of AD by reducing lncExACT1.

These hypotheses will be tested in two Specific Aims. In Aim 1 we will examine the correlation between brain lncExACT1 expression and severity of cognitive dysfunction and central nervous system pathology in AD patients and APP/PS1 mice in comparison to controls. In Aim 2, we will characterize the biological roles of

brain lncExACT1 in vivo in wild-type mice and the APP/PS1 AD mouse model using AAV-mediated overexpression and modified antisense oligonucleotide-mediated inhibition. Effects on cognitive performance and brain pathology will be assessed. Successful completion of the proposed studies would provide new insights into the shared biology of the heart and the brain, and point to mechanisms driving

coordinated responses to pathological and physiological stimuli in both organs. Most importantly, successful completion of these studies would support further investigation of lncExACT1 as a much-needed therapeutic target in patients with AD and other forms of cognitive dysfunction.