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

> **NIH NIH R03** · UNIVERSITY OF ALABAMA AT BIRMINGHAM · 2020 · $74,250

## Abstract

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 In our unpublished study, we used the cardiac troponin T (cTnt)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.

## Key facts

- **NIH application ID:** 9991725
- **Project number:** 5R03AG064652-02
- **Recipient organization:** UNIVERSITY OF ALABAMA AT BIRMINGHAM
- **Principal Investigator:** KAI JIAO
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $74,250
- **Award type:** 5
- **Project period:** 2019-08-15 → 2022-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9991725

## Citation

> US National Institutes of Health, RePORTER application 9991725, Test the role of cardiac expressed SEMA6D in Alzheimer's disease (5R03AG064652-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9991725. Licensed CC0.

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