Test the role of cardiac expressed SEMA6D in Alzheimer's disease

摘要 本研究的主要目的是测试使用小鼠模型来检查 先天性心脏病（CHD）对阿尔茨海默病（AD）的发病和进展的影响。冠心病是最常见的 常见的结构性出生缺陷，发生在1-5%的新生儿。由于大大改善了诊断和 根据治疗策略，约90%患有CHD的儿童现在可以存活至成年。成人CHD患者现在 与儿童CHD患者的比例为2：1。越来越多的成年冠心病患者正在老龄化， 新的医疗挑战在照顾这些病人。2018年发表的一项全国流行病学研究 显示患有CHD的成年人与普通人相比，患AD的风险显著增加。 老年痴呆症的发病率在老年人中较高，而老年痴呆症的发病率在老年人中较高。因此，早期异常 胚胎/新生儿的心脏发育显著增加了以后发展为痴呆/AD的风险。的 冠心病与AD发病间隔较长，这使得研究冠心病与AD的相互作用成为可能 极具挑战性。因此，这并不完全令人惊讶的是，很少，如果有的话，这样的研究可以在文献中找到。 考虑到CHD和AD都已经通过小鼠遗传学进行了大量研究，我们建议开发 小鼠模型来研究CHD如何影响AD。在我们未发表的研究中，我们使用了心肌肌钙蛋白T（cTnT） -Cre驱动程序在胚胎心脏中特异性抑制Sema 6D。突变小鼠表现出发育不良 由于心肌细胞增殖减少，P0时心肌壁缺损。我们计划将Sema 6D 敲除小鼠与完善的AD模型系APPNL-G-F/NL-G-F敲入小鼠，以检查 先天性心肌病对小鼠AD样缺陷的影响我们的中心假设是先天性心肌病 由胚胎心脏引起的Sema 6D缺失加速了AD相关的发病并加重了AD的严重程度。 AD小鼠的缺陷。我们将在目的1和2中检查这些小鼠的认知和神经病理学缺陷， 分别该项目本质上具有很强的创新性。冠心病是一种新发现的AD危险因素。评价 CHD如何影响AD是AD研究的一个全新领域。我们的研究代表了第一个测试 使用小鼠模型研究CHD-AD相互作用的可行性。成功完成我们的研究将 为该领域未来的体内研究打开了大门。

Abstract The primary goal of this research is to test the feasibility of using mouse models to examine the effect of congenital heart diseases (CHDs) on the onset and progression of Alzheimer’s disease (AD). CHDs are the most common structural birth defects, occurring in 1-5% of newborns. Owing to the greatly improved diagnostic and therapeutic strategies, ~90% of children with CHDs can now survive to adulthood. Adult CHD patients now outnumber pediatric CHD patients by a ratio of 2:1. A growing number of adult CHD patients are aging, posing new medical challenges in caring for these patients. A nationwide epidemiological study published in 2018 revealed that adults with CHDs have a significantly increased risk for developing AD compared to the general population, and that the risk is particularly increased for early onset of dementia. Therefore, the early abnormal heart development in embryos/neonates significantly increases the risk of later developing dementia/AD. The long interval between the occurrence of CHDs and the onset of AD makes studies of the CHD-AD interaction highly challenging. Thus, it is not entirely surprising that few, if any, such studies can be found in the literature. Considering that both CHDs and AD have been heavily studied through mouse genetics, we propose to develop mouse models to examine how CHDs affect AD. In our unpublished study, we used the cardiac troponin T (cTnt) –Cre driver to specifically inactivate Sema6D in embryonic hearts. Mutant mice displayed the hypoplastic myocardial wall defect at P0 due to reduced cardiomyocyte proliferation. We plan to crossbreed Sema6D knockout mice with a well-established AD model line, APPNL-G-F/NL-G-F knock-in mice, to examine the impact of inborn cardiomyopathy on AD-like deficits in mice. Our central hypothesis is that congenital cardiomyopathy caused by embryonic heart deletion of Sema6D accelerates the onset and exacerbates the severity of AD-related deficits in AD mice. We will examine the cognitive and neuropathological defects in these mice in Aims 1 and 2, respectively. This project is highly innovative by nature. CHD is a newly identified risk factor for AD. Evaluating how CHDs impact AD is a completely new area for AD research. Our study represents the first to test the feasibility of using mouse models to study the CHD-AD interaction. Successfully accomplishing our research will open the door for future in vivo studies in this field.