Hypertension is one of the most prevalent cardiovascular disorders worldwide, affecting 1.13 billion people, or 14% of the global population. Hypertension is the single biggest risk factor for cerebrovascular dysfunction. According to the American Heart Association, high blood pressure (BP), especially in middle-aged individuals (~ 40 to 60 years old), is associated with an increased risk of dementia, later in life. Alzheimer’s disease and cerebrovascular disease are the two leading causes of dementia, accounting for around 80% of the total cases and usually combining mixed pathologies from both. Little is known regarding how hypertension affects cognitive function, so the impact of its treatment on cognitive impairment has been difficult to assess. The brain renin-angiotensin system (RAS) is essential for BP regulation and overactivity of this system has been established to precede the development and maintenance of hypertension. Angiotensin II (Ang-II), the main peptide within this system, induces vasoconstriction and impairs neuro-vascular coupling by acting on brain Ang-II type 1 receptors (AT 1 R). In this review, we systemically analyzed the association between RAS and biological mechanisms of cognitive impairment, from the perspective of AT 1 R located in the central nervous system. Additionally, the possible contribution of brain AT 1 R to global cognition decline in COVID-19 cases will be discussed as well.
Hypertension is one of the most prevalent cardiovascular diseases worldwide and is known to be dominated by the sympathetic nervous system (SNS). Previously, we found that targeting A Disintegrin and Metalloproteinase 17 (ADAM17) in glutamatergic neurons was able to blunt Ang-II-induced excitation of pre-autonomic neurons, and blocked DOCA-salt treatment-induced sympatho-excitation in mice, thereby alleviating their development of hypertension. However, how ADAM17 support the activation of pre-autonomic neurons remains unknown. Beyond the glutamatergic neurons, we found in the current study that microglial activation and increase of pro-inflammatory cytokine levels in the hypothalamus, induced by DOCA-salt treatment, were blunted in those mice with ADAM17 knockout in glutamatergic neurons (A17G; number of CD11b+cells per line: NT+DOCA vs. A17G+DOCA= 11±2 vs. 6±1, P= 0.0017; normalized TNFα level: NT+DOCA vs. A17G+DOCA= 1.00±0.37 vs. 0.67±0.11, P< 0.05; normalized IL-6 level: 1.00±0.32 vs. 0.59±0.20, P< 0.05). Especially, it also reversed DOCA-salt-induced downregulation of Gad67 mRNA expression (NT= 1.00±0.11, NT+DOCA= 0.66±0.12, A17G= 1.02±0.15, A17G+DOCA= 1.67±0.24 fold of change, NT vs. NT+DOCA and A17G vs. A17G+DOCA: P< 0.05), and normalized the decreased level of GABA in hypothalamus (normalized GABA levels: NT= 1.00±0.15, NT+DOCA= 0.84±0.09, A17G+DOCA= 1.09±0.17, NT vs. NT+DOCA: P< 0.05), suggesting that in addition to the effect of ADAM17 on the neuron itself, it might also regulate the SNS through altering the neuronal microenvironment. In L-NAME hypertensive model, though A17G mice showed no improvement in NOS-blockade-induced dysfunction of neuro-vascular coupling (increase of CBF induced by whisker-stimulation: NT vs. A17G= 24.34±11.20 vs. 24.87±15.78 PU%), it did exhibit improved performance in Barnes maze test (latency time: NT vs. A17G= 32.77±19.36 vs. 95.54±59.03 s, P= 0.002), suggesting that ADAM17 in glutamatergic is critical for the process of neuronal damage induced by hypoxia and ischemia, possibly through modulating the homeostasis of neuronal microenvironment.
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.
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