Salt-sensitive hypertension promotes neuronal mitochondrial stress and neurodegenerative alterations via neuro-vascular metabolic reprogramming and local RAS signaling

作者：Hanxue Wu, Zihan Qiu, Junya Mu, Yi Wang, Jiawei Wang, Yue Han, Ruijie Yang, Shenglan Yuan, Yuan Miao, Rui Yang, Xingjuan Chen, Qi Sun, Fanni Li, Lei Xiao, Ming Zhang, Jiaxi Xu · 发表于：Journal of Neuroinflammation · 年份：2025 · DOI：10.1186/s12974-025-03533-0 · 被引用次数：2 · 研究领域：Birth, Development, and Health、Apelin-related biomedical research、Diet and metabolism studies

Hypertension increases risks for cognitive impairment and Alzheimer’s disease (AD). In renal patients with both hypertension and cognitive decline, via rest-state fMRI, their cerebral cortical region showed maintained cerebral blood flow (CBF), but reduced signals of blood-oxygen-level-dependent (BOLD). In mice, although CBF was unchanged, deoxycorticosterone acetate (DOCA)-salt treatment markedly reduced cerebrovascular reactivity, with altered transcriptomic pattern in cortical endothelial cells (ECs) and astrocytes, showing downregulated expression of glucose transport 1 (GluT1) but upregulated metabolic reprogramming. Lipidomic analysis using prefrontal cortex (PFC) further revealed enhanced catabolism of glycerophospholipids and accumulation of free fatty acids. In the PFC of hypertensive mice, neurodegenerative alterations were observed, including reduced number of neuronal dendritic spines and more expression of phosphorylated Tau (p-Tau). Via both morphological and molecular tests, we identified that DOCA-salt hypertension was associated with significant mitochondrial injury and upregulated lysine succinylation in the PFC neurons. Upregulated lysine succinylation was largely mitochondria-located, and they were functionally enriched in gluconeogenesis-related energy metabolic pathways, the tricarboxylic acid (TCA) cycle, oxidative stress, and neurodegenerative diseases. In hypertensive mice, angiotensinogen (Agt) expression was markedly upregulated in most astrocytes, ...