Abstract P076: Cerebral Vascular Dysfunction Precedes Cognitive Impairment In Alzheimer’S Disease

Abstract

Alzheimer’s disease (AD) is the most common form of dementia and is a major financial burden to the health care system. The prevailing view is that cholinergic deficiency, amyloid-beta (Aβ) accumulation, and Tau protein abnormalities are the primary underlying causes of neurodegeneration in AD, but unsuccessful clinical trials targeting these pathways have led the community to reconsider alternatives such as the vascular hypothesis. However, it is still uncertain whether cerebral vascular impairment is a cause or consequence of dementia in AD. Previous studies have demonstrated that a TgF344-AD model expressing mutant human amyloid precursor protein ( APP ) and presenilin 1 ( PS1 ) genes exhibits Aβ accumulation and cognition deficiency at 24 weeks of age. In the present study, we compared the myogenic response (MR) of the middle cerebral artery (MCA) and parenchymal arteriole (PA) in 8-, 16- and 24-week TgF344-AD and WT F344 rats. We first confirmed that TgF344-AD rats exhibited learning and memory dysfunction at 24-week of age, and they took 2-time longer to escape than WT rats using an eight-arm water maze. There was no difference in the MR of MCA and PA at 8 weeks of age in AD and WT rats. However, AD rats exhibited an impaired MR at 16-week of age as the inner diameter of the MCA of AD rats only decreased by 6.6 ± 1.7% vs. 10.7% ± 1.0% in WT rats when perfusion pressure was increased from 40 to 180 mmHg. The impaired MR was exacerbated in AD rats at 24-week of age. These findings suggest that impaired MR of cerebral vasculature precedes the development of a cognitive deficiency. Since the MR protects the cerebral microcirculation from elevations in pressure, an impaired MR and cerebral blood flow autoregulation could result in blood-brain barrier leakage that contributes to neurodegeneration and cognitive impairment. Our results provide novel insight in understanding the pathogenesis of AD, which will lay the foundation for the discovery of new biomarkers in AD.