BDNF TrkB- and beta-AR signals in ischemic and non-ischemic cardiomyopathy

项目总结

Project Summary Alzheimer’s disease (AD) and heart failure with preserved ejection fraction (HFpHF) are highly prevalent diseases. Recent findings show the alarming prospective that they can intertwine in the same individuals. For both conditions, the therapeutic options remain scant. Following the NIH initiative directed to penetrate the pathogenesis of either of these diseases to unearth more effective therapeutic options, here we propose to investigate a new mechanism that AD and HFpEF may have in common and that can unveil a unifying therapeutic approach for both diseases. That is: that the concomitant cardiac and central loss in brain-derived neurotrophic factor (BDNF) and its associated receptor, tropomyosin receptor kinase B (TrkB) accounts for Aβ pathology and hyperphosphorylated tau deposition and vice-versa, contributing to the onset and progression of AD and HFpHF. In turn, these two conditions negatively reverberate on each other. Here, we propose two aims. In the first Aim, using unique gene-edited mouse lines for cardiac and neuronal BDNF/TrkB signaling, we will determine whether a lack of TrkB/BDNF signaling fuels Aβ and/or tau pathology, triggering HFpEF and, in turn, the accumulation of Aβ and/or tau in the heart underlies HFpEF pathogenesis via reduced expression of TrkB/BDNF signaling. In the second Aim, we will test the impact of specific, agonist-based TrkB stimulation prevents the accumulation of Aβ and hyperphosphorylated tau in the heart and brain of AD, improving both cognitive/locomotor and diastolic dysfunction.Of note, in the present proposal, we will put the evaluation of myocardial performance on equal footing with that of central functions. Indeed, in all mouse protocols performed here, we will conduct behavioral studies apt to evaluate cognitive abilities (such as short- and long-term memory) and mood control (anxiety and depression) to determine whether an improvement of cardiac function via TrkB agonists attenuates behavioral alterations typically found in patients with AD or HFpEF, or vice versa. The functional parameters will be also paralleled by the biochemical and pathological assessment, key for the diagnosis of proteinopathies and for the analysis of the mechanisms.