Hypertension has now been considered as one of the risk factors of Alzheimer's disease (AD), due to its contribution to the dysfunction of cerebrovascular system. To investigate its neuronal contribution, hypertension was induced in C57BL/6j male mice by either systemic infusion of Ang-II (600 ng/kg/min, s.c., 14 days) or DOCA-salt treatment (1 mg/g, s.c., 21 days), then markers for neuronal function were measured via qRT-PCR. In the hippocampus, Ang-II treatment significantly down-regulated the mRNA levels of BDNF (brain-derived neurotrophic factor) and DLG4 (discs large homolog 4, encoding PSD95), while DOCA-salt treatment only down-regulated BDNF expression (P<0.05 vs. sham, n=6). Notably, the expression of PI4KIIIβ, a key kinase for phosphatidylinositol-4,5-isphosphate (PIP
2
) re-synthesis, was found to be markedly down-regulated in the hippocampus of both hypertension models (P<0.05 vs. sham, n=6). PI4K activity has been closely associated with 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 have demonstrated that neuronal AT
1
R plays pivotal role in the maintenance of neurogenic hypertension, and here we hypothesized that activation of AT
1
R 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 AT
1a
R, 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 AT
1
R in AD, 5хFAD mice were bred with mice with neuronal AT
1
R deletion (AT1NKO). AD-associated reduction of ACE2 protein, mainly in neurons, was found to be slightly ameliorated in the prefrontal cortex of 5хFAD-AT1NKO, compared to the age/sex-matched 5хFAD, showing by immunocytochemistry (24610 ±4182 vs. 13420 ±3720 AFU, n=6 slices). Although the detailed mechanism is still unknown, our data suggest that, neuron-expressing AT
1
R could participate in the development of hypertension-associated cognitive impairment and AD, independently of vascular AT
1
R.
A novel enhancer that regulates Bdnf expression in developing neurons
