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Hypertension Promotes Neuroinflammation, Brain Injury and Cognitive Impairment

ABSTRACT: We tested the effect of hydralazine on hypertension-induced transciptomic changes in hippocampus and a whole brain hemisphere.

ORGANISM(S): Mus musculus

PROVIDER: GSE261492 | GEO | 2025/12/31

REPOSITORIES: GEO

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Project description:Hypertension (HTN) has been associated with cerebrovascular dysfunction and cognitive impairment. To understand how HTN affects the brain, the coupling between oxygen consumption and cerebral blood flow in multiple brain regions was firstly analyzed using functional MRI, in patients with HTN and healthy controls. It indicated less functional hyperemia in the cortical areas of HTN group, but showed no difference in their hippocampus. We then used deoxycorticosterone acetate (DOCA)-salt model, in which HTN is developed via sympathetic overactivity, and confirmed HTN-associated cognitive decline and reduction in functional hyperemia of pia arterioles in both male and female mice. Notably, maze test-based cognitive function was partially protected in female mice. In the sensory cortex and hippocampus of male HTN mice, we detected higher reactiveness of glial cells, compared to sham controls. But microglia in the hippocampus reacted more to DOCA-salt, showing a sub-population characterized by high expression of Apoe, B2m, Ramp1, and S100a8/a9, which was not detected in the cortex. With further analyzing the gene profile of immune cells, it revealed disease-associated types of monocyte and macrophage only in the hippocampus, and pinpointed an involvement of peripheral reservoir of immune cells. Next, to determine possible contribution from sympathetic agitation of the peripheral immune system, we tested mice lacking neuron-expressed type 1 angiotensin-II receptors (AT1R), a line that previously showed blunted sympathoexcitation under DOCA-salt treatment. In addition to improved cognitive function, DOCA-salt-induced upregulation of glial reactiveness and pro-inflammatory markers were not seen, and Bdnf expression was preserved in the hippocampus of those mice. To test the role of spleen, which deployed leukocytes upon splenic sympathoexcitation in DOCA-salt HTN, splenectomy was performed and it attenuated hippocampal inflammation and cognitive impairment, in a similar manner as neuronal AT1R knockout. Together, our data provide evidence that the cortex and hippocampus were differently affected by HTN, and proposed a neural mechanism for HTN-associated cognitive impairment that involves sympathoexcitation-induced immune response, thus highlighting that autonomic regulation of the immune system could be a therapeutic target for improving hippocampal health during HTN.

Project description:Intracerebral hemorrhage (ICH) is a significant health concern associated with high mortality. Cofilin plays a crucial role in stress conditions, but its signaling following ICH in a longitudinal study is yet to be ascertained. In the present study, we examined the cofilin expression in human ICH autopsy brains. Then, the spatiotemporal cofilin signaling, microglia activation, and neurobehavioral outcomes were investigated in a mouse model of ICH. Human autopsy brain sections from ICH patients showed increased intracellular cofilin localization within microglia in the perihematomal area, possibly associated with microglial activation and morphological changes. Various cohorts of mice were subjected to intrastriatal collagenase injection and sacrificed at time points of 1, 3, 7, 14, 21, and 28 days. Mice suffered from severe neurobehavioral deficits after ICH, lasting for 7 days, followed by a gradual improvement. Mice suffered post-stroke cognitive impairment (PSCI) both acutely and in the chronic phase. Hematoma volume increased from day 1 to 3, whereas ventricle size increased from day 21 to 28. Cofilin protein expression increased in the ipsilateral striatum on days 1 and 3 and then decreased from days 7 to 28. An increase in activated microglia was observed around the hematoma on days 1 to 7, followed by a gradual reduction up to day 28. Around the hematoma, activated microglia showed morphological changes from ramified to amoeboid. mRNA levels of inflammatory [tumor necrosis factor-α (TNF-α), interleukin 1β (IL-1β), and interleukin-6 (IL-6) and anti-inflammatory markers [interleukin-10 (IL-10), transforming growth factor-β TGF-β, and arginase I (Arg1)] increased during the acute phase and decreased in the chronic phase. Blood cofilin levels increased on day 3 and matched the increase in chemokine levels. slingshot protein phosphatase 1 (SSH1) protein, which activates cofilin, was increased from day 1 to 7. These results suggest that microglial activation might be the sequel of cofilin overactivation following ICH, leading to widespread neuroinflammation and consequent PSCI.

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Hypertension Promotes Neuroinflammation, Brain Injury and Cognitive Impairment

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