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

项目摘要 阿尔茨海默病(AD)和射血分数保留的心力衰竭(HFPHF) 流行的疾病。最近的发现显示了令人担忧的前景，即它们可以在 同样的个体。对于这两种情况，治疗选择仍然很少。跟随美国国立卫生研究院 旨在深入了解这两种疾病的发病机制，以发掘更多 有效的治疗选择，在这里，我们建议研究一种新的机制，即AD和 HFpEF可能有共同之处，可以为两者揭示一种统一的治疗方法 疾病。即：脑源性神经营养中伴随的心脏和中枢丢失 脑源性神经营养因子及其相关受体原肌球蛋白受体激酶B(TrkB)参与A-β 病理和过度磷酸化的tau沉积，反之亦然。 AD和HFPHF的进展。反过来，这两种情况又会相互产生负面影响。 在这里，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来研究心脏 以及神经元的BDNF/TrkB信号，我们将确定是否缺少TrkB/BDNF信号 刺激β和/或tau病理，触发HFpEF，进而积聚aβ和/或tau 在心脏中，HFpEF的发病机制是通过TrkB/BDNF信号的表达减少来实现的。在……里面 第二个目标，我们将测试特定的、基于激动剂的TrkB刺激预防 Aβ和过度磷酸化tau在AD患者心脏和大脑中的积聚，改善两者 认知/运动和舒张期功能障碍。需要注意的是，在本提案中，我们将把 在与中枢功能相同的基础上评价心肌功能。的确，在所有方面 在这里执行的小鼠协议，我们将进行行为研究，以评估认知 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激动剂改善心功能是否会减弱行为 AD或HFpEF患者通常会出现改变，反之亦然。功能参数 也会同时进行生化和病理评估，是诊断本病的关键 蛋白质病及其机制的分析。

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.