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

摘要 这项研究的主要目的是测试使用小鼠模型检查的影响的可行性 先天性心脏病(CHDS)对阿尔茨海默病(AD)发生和发展的影响。CHDS是最多的 常见的结构性出生缺陷，发生在1-5%的新生儿中。由于大大改进了诊断和 治疗策略，约90%的先天性心脏病儿童现在可以存活到成年。现在的成年冠心病患者 儿童冠心病患者的数量与儿童冠心病患者的数量之比为2：1。越来越多的成年冠心病患者正在老龄化， 在照顾这些患者方面面临着新的医学挑战。2018年发表的一项全国性流行病学研究 研究显示，与普通人群相比，患有先天性心脏病的成年人患AD的风险显著增加 他说，这与人口数量有关，而且早发痴呆症的风险尤其高。因此，早期的异常 胚胎/新生儿的心脏发育显著增加了日后发展为痴呆症/AD的风险。这个 冠心病的发生和AD发病之间的长时间间隔使得对CHD-AD相互作用的研究成为可能 极具挑战性。因此，在文献中几乎找不到这样的研究也就不足为奇了。 考虑到CHDS和AD都已通过小鼠遗传学进行了大量研究，我们建议开发 研究CHD如何影响AD的小鼠模型。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，专门灭活胚胎心脏中的Sema6D。突变小鼠表现出发育不良 P0的心肌壁缺陷是由于心肌细胞增殖减少所致。我们计划杂交Sema6D 用已建立的AD模型系APPNL-G-F/NL-G-F基因敲除小鼠，考察其对AD模型小鼠的影响 先天心肌病对小鼠AD样缺陷的影响。我们的中心假设是先天性心肌病 胚胎心脏Sema6D缺失加速AD发病加重 阿尔茨海默病小鼠的缺陷。我们将在AIMS 1和AIMS 2中检查这些小鼠的认知和神经病理缺陷， 分别进行了分析。这个项目本质上是高度创新的。冠心病是新发现的AD危险因素。正在评估 CHDS如何影响AD是AD研究的一个全新领域。我们的研究是第一次测试 用小鼠模型研究CHD-AD相互作用的可行性。成功地完成我们的研究将会 为这一领域未来的活体研究打开大门。

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 In our unpublished study, we used the cardiac troponin T (cTnt) –Cre driver to specifically inactivate Sema6D in embryonic hearts.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.