Activation of neuronal AT 1 R exacerbates hypertension‐induced cognitive impairment through decreasing neuronal function

Abstract

Hypertension has now been closely associated to cognitive impairment and considered as one of the risk factors of Alzheimer's disease (AD), due to its contribution to cerebrovascular dysfunction. To investigate whether there is neuronal mechanism, hypertension was induced in C57BL/6j male mice (6 months) by DOCA-salt treatment (1.5 mg/g, s.c., 28 days). Firstly, behavioral study, which contains novel object recognition (NOR) and nesting score tests, was performed to assess cognitive function. DOCA plus 1% NaCl in the drinking water significantly increased the blood pressure (BP) of treated control mice (normal type, NT), before vs. after DOCA (tail-cuff, systolic BP): 114.4 ±2.0 vs. 130.8 ±1.9 mmHg. At the end of DOCA-salt treatment, both NOR% [(timenovel-timeold)/(timenovel+timeold)×100%] and nesting scores were markedly reduced in NT mice, compared to their baselines, indicating impaired cognitive function (NOR%: 10.83 ±7.413% vs. 39.46 ±8.926%, n=13; nesting scores: 3.1 ±0.23 vs. 5, n=10). Later on, brain tissues were collected, and markers for neuronal function were measured via qRT-PCR. In both of the prefrontal cortex and hippocampus, it was found that the mRNA levels of BDNF (brain-derived neurotrophic factor) and PI4KIIIβ (phosphatidylinositol 4-kinase IIIβ) were significantly down-regulated, in those NT mice with DOCA-salt hypertension (cortical Bdnf: P<0.001 vs. sham, cortical Pi4k: P<0.001 vs. sham, hippocampal Bdnf: P<0.001 vs. sham, hippocampal Pi4k: P<0.05 vs. sham, n=7). Noteworthy, PI4K has been linked to the progression of neurodegenerative disorders, especially AD, therefore suggesting that reduction of neuronal function could be a part of the etiology of hypertension-related cognitive decline. We previously demonstrated that neuronal AT1R plays pivotal role in the maintenance of neurogenic hypertension, and here we hypothesized that activation of AT1R could also exacerbate hypertension-induced reduction in neuronal function. In mice with DOCA-salt hypertension, the function of cortical neurons was shown to be improved by selective deletion of neuronal AT1aR, as evidenced by significantly higher mRNA levels of BDNF and PI4KIIIβ, compared to the controls (P<0.05 vs. sham, n=6). To further study the possible involvement of neuronal AT1R in AD, 5×FAD mice were bred with mice with neuronal AT1R deletion (AT1NKO). AD-associated reduction of ACE2 protein, mainly in neurons, was found to be slightly ameliorated in the prefrontal cortex of 5×FAD-AT1NKO, compared to the age/sex-matched 5×FAD, showing by immunocytochemistry (24610 ±4182 vs. 13420 ±3720 AFU, n=6 slices). Although the detailed mechanism is still unknown, our data suggests that, neuron-expressing AT1R could participate in the development of hypertension-associated cognitive impairment, independently of vascular AT1R.