Cerebral Vascular Smooth Muscle Cells Exhibit an Endogenous Diminished Contractile Capability in TgF344‐AD Rat Model of Alzheimer's Disease.

R1943 --> We recently reported that cerebral vascular dysfunction precedes cognitive impairment in TgF344‐AD (AD) rat model of Alzheimer's disease. However, whether abnormalities in cerebral vascular smooth muscle cells (VSMCs) play a direct role has not been studied. In the present study, we first confirmed that the AD rats started to develop learning and memory deficits at 24‐week of age using an eight‐arm water maze. AD rats (n = 11) took a longer time to escape and displayed more errors than age‐matched wildtype (WT) rats (n = 6). We also completed a longitudinal comparison of the myogenic response (MR) of the middle cerebral artery (MCA) and found that the MR was similar in AD and WT rats at 8‐ to 12‐week of age when perfusion pressure was increased from 40 to 180 mmHg. However, the MR started first became significantly reduced in 16‐week old AD rats (n = 6) as the inner diameter of the MCA only decreased by 8.2 ± 2.4% when perfusion pressure was increased from 40 to 180 mmHg compared with 14.5% ± 2.0% in age‐matched WT rats (n = 6). The impaired MR of the MCA was exacerbated in AD rats with aging. Consistent with the exvivo MR studies, in vivo experiment using a laser‐Doppler flowmeter demonstrated that the cerebral blood flow (CBF) autoregulation of AD rats (n = 4) was impaired in the surface and deep cortex at 24‐week of age compared to age‐matched WT rats (n = 4). Furthermore, we found an endogenous reduced cell contractile capability in the cerebral VSMCs isolated from AD (n = 4) compared with WT rats (n = 4), detected by a maximal gel size reduction by 15.7 ± 0.9% vs. 25.4 ± 1.0% using a collagen gel‐based assay kit. These results provide evidence that cerebral VSMC dysfunction, impaired MR and autoregulation of CBF correlates, which precedes the development of memory and learning deficits in the TgF344‐AD rats. However, the underlying mechanisms causing the loss of VSMCs contractility in this AD model expressing mutant human amyloid precursor protein (APPsw) and presenilin 1 (PS1ΔE9) genes remains to be determined. Nevertheless, these results provide novel insight into vascular contribution to AD, which will lay the foundation for the discovery of new biomarkers in AD. [ABSTRACT FROM AUTHOR]