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

项目摘要 阿尔茨海默病（AD）和射血分数保留性心力衰竭（HFpHF）是高度危险的。 流行病。最近的研究结果显示，它们可以干预 相同的个体。对于这两种情况，治疗选择仍然很少。根据NIH 该倡议旨在深入了解这些疾病的发病机制， 有效的治疗选择，在这里，我们建议调查一个新的机制，AD和 HFpEF可能有共同之处，这可以揭示两者的统一治疗方法 疾病也就是说：脑源性神经营养因子中伴随的心脏和中枢损失 Aβ由脑源性神经营养因子（BDNF）及其相关受体原肌球蛋白受体激酶B（Trk B）介导 病理学和过度磷酸化的tau沉积，反之亦然，有助于发病， AD和HFpHF的进展。反过来，这两种情况又相互产生负面影响。 在此，我们提出两个目标。在第一个目标中，使用独特的基因编辑小鼠系进行心脏 和神经元BDNF/TrkB信号传导，我们将确定TrkB/BDNF信号传导的缺乏是否会导致神经元BDNF/TrkB信号传导的缺失。 刺激Aβ和/或tau病理学，触发HFpEF，进而导致Aβ和/或tau的积累 在心脏中，通过减少TrkB/BDNF信号传导的表达，是HFpEF发病机制的基础。在 第二个目标，我们将测试特异性的、基于激动剂的TrkB刺激的影响， Aβ和过度磷酸化的tau蛋白在AD的心脏和大脑中的积累， 认知/运动和舒张功能障碍。值得注意的是，在本提案中，我们将把 心肌功能评价与中枢功能评价同等重要。事实上， 在这里进行的小鼠实验中，我们将进行行为研究，以评估认知能力。 能力（如短期和长期记忆）和情绪控制（焦虑和抑郁）， 确定通过TrkB激动剂改善心脏功能是否减弱行为 在AD或HFpEF患者中通常发现的改变，反之亦然。功能参数 还将通过生化和病理评估进行评估，这是诊断的关键。 蛋白质病和机制的分析。

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.