Abstract WP532: Hypertension Interacts With Alzheimer’S Disease via Autophagy-related Phenotypic Changes in Vascular Endothelial Cells

Abstract

Alzheimer's disease (AD) is characterized by a progressive neuronal disorder that causes dementia, and is recognized as the leading cause of death in the elderly population. The typical features of AD are Aβ (β amyloid) -containing plaques in the diseased brain. Recent clinical and epidemiological evidences suggest that hypertension, a major vascular risk factor, is possibly implicated in neurodegenerative AD. However, the mechanistic interaction between hypertension and AD is mostly unclear. Here, we investigate whether the mutual phenotypic changes of brain vascular endothelium are existed in AD and hypertension. In this study, 8 or 24 month old male APP23 mice, which represent cognitive disturbance, were used as an in vivo model of AD. 8 week old male Spontaneous hypertensive rats (SHR) and the Wister Kyoto rats (WKY) were used as hypertensive animal and those genetic controls, respectively. Aortic ring assay was performed as ex vivo model of endothelial function. Human endothelial cells (EC) were cultured with Aβ40, H2O2, or cyclic mechanical stretch. Immunohistological staining and EM analysis were performed on brain and aortic tissues or cultured human EC. We found that the hippocampal vessel densities were significantly lower in APP23 mice as compared to those in wild type. Importantly, autophagy, a self-eating process, was detected in hippocampal capillary endothelium in 8-month old APP23 mice, and the number of autophagic microvessels was significantly increased in 24-month-old APP23 mice. The advanced stages of autophagy fused with lysosome were also detected in neurovascular endothelium in APP23 mice. Notably, consistent with the findings in APP23 mice, autophagy was also detected in hippocampal endothelium of SHR, but not in WKY. Aortic ring assay showed that endothelial potential for regeneration was impaired in SHR as compared with those in WKY. Furthermore, Aβ40, H2O2, or cyclic mechanical stretch not only induced autophagy but also impaired endothelial proliferation and NO production in cultured ECs. In conclusion, present findings indicate that phenotypic changes of endothelium, characterized by autophagy induction and impaired endothelial function might be the reciprocal mechanistic interaction between AD and hypertension.