Abstract 092: Activation Of Neuronal At 1 R Exacerbates Hypertension-associated Mci Through Vascular And Neural Mechanisms

Abstract

Hypertension (HTN) has now been associated with cognitive impairment and considered as one of the risk factors for mild cognitive impairment (MCI). To investigate whether there is neuronal mechanism, HTN was induced in C57BL/6j male mice (~22 weeks) by DOCA-salt treatment (DS, 1.4mg/g+1%NaCl, 28 days), a neurogenic model. Firstly, BP was monitored by tail-cuff (sham vs. DS: SBP= 116.1±7.6 vs. 145.0±8.2 mmHg). Then, behavioral study was performed to assess the cognitive function (CFN). In whole, compared to sham, the DS mice performed worse in all 4 tasks, including object location recognition (before vs. after: NLR%= 29.34±13.73 vs. -20.81±10.70), novel object recognition (NOR%= 48.60±22.62 vs. 9.09±25.50), Barnes maze (latency T= 26.55±16.52 vs. 116.80±57.67s), and nesting (score= 4.00±0.92 vs. 2.43±1.55). Later, CBF was measured by laser doppler. The rise of CBF upon whisker-stimulation (WS) was lower in the DS mice (27.83±13.86 vs. 51.12±18.22 PU), while their basal CBF was not affected, suggesting that DS-induced MCI could be related to impairment of neuro-vascular coupling (NVC). Previously, we have showed the overactivation of brain renin-angiotensin system (RAS) in the onset of DS HTN. To identify the possible contribution from brain RAS, neuronal AT 1a R were deleted (AT1N). In AT1N mice, DS-related impairments in CFN and NVC were attenuated, as evidenced by higher nesting scores (AT1N+DS vs. NT+DS: 3.75±1.89 vs. 2.43±1.55 ), better performance in Barnes maze (61.28±54.47 vs. 116.80±57.67 s) and grater augment in CBF upon WS (41.49±10.65 vs. 27.83±13.86 PU), compared to NT. Through LTP recording in CA1 neurons using both field and whole-cell modes, we identified that activation of neuronal AT 1 R could contribute directly to the development of MCI, thereby neuronal AT 1 R was selectively knocked down in the hippocampus of NT mice (AT1hN). After DS treatment, AT1hN showed no difference in SBP compared with the sham NT (149.0±14.7 vs. 150.4±6.9 mmHg), while their CFN showed improvement in both NOR and Barnes maze (NOR%= 11.70±25.78 vs. -10.15±42.60; latency T= 71.72±47.60 vs. 113.70±65.64 s). In summary, our data suggest that neuron-expressing AT 1 R could participate in the onset of hypertension-associated MCI via both vascular and neural mechanisms.