Targeting NDUFS8 in basal forebrain ameliorates cognitive decline related to chronic cerebral hypoperfusion.

Abstract

Chronic cerebral hypoperfusion (CCH), characterized by sustained cerebral ischemic-hypoxic damage due to chronically reduced cerebral blood flow, represents an established risk factor for cognitive decline. While basal forebrain and mitochondrial homeostasis are both vulnerable to hypoperfusion, the precise molecular mechanisms underlying CCH-induced mitochondrial dysfunction in this brain region remain elusive.Integrating transcriptomic-proteomic analysis of human dementia cohorts to determine the role of NDUFS8 in hypoperfusion-induced cognitive deficits. Stereotaxic injection of AAV vectors encodingshRNA or overexpression constructs to induce loss- or-gain-of-function of NDUFS8 in the basal forebrain. Multiscale analyses combining dual-luciferase reporter assays, chromatin immunoprecipitation and computational simulations to reveal the regulatory mechanism of NRF2 on NDUFS8.Our study suggests that NDUFS8 was the most significantly downregulated mitochondrial gene with strong clinical correlation in dementia patients, this was also verified in the basal forebrain of postmortem AD specimens and CCH rats. Basal forebrain-specific NDUFS8 restoration rescued spatial memory deficits in CCH rats through enhancing mitochondrial oxidative phosphorylation function. Mechanistically, multiscale analyses revealed a novel dual regulatory paradigm: NRF2 exhibited impaired binding capacity to both antioxidant response element (ARE) and non-ARE motifs in thepromoter, while cytoplasmic NRF2 deficiency compromised its stabilizing effect on NDUFS8 protein.Overall, our results indicate that NRF2-NDUFS8 regulatory axis as a major coordinator of mitochondrial homeostasis during hypoperfusion and identify this pathway as a novel therapeutic direction for improving CCH-related cognitive deficits.