Aortic aneurysm and dissection and its multidimensional impact on cognitive function: The pivotal role of PRDX6 in pathophysiological mechanisms.

AIMS: This study aims to explore the relationship between aortic aneurysm and dissection (AAD) and cognitive impairment, with an emphasis on uncovering the potential biological mechanisms.

METHODS

Utilizing the UK Biobank database, a matched cohort study was performed to assess the association between AAD and the risk of Alzheimer's disease. Cognitive function was evaluated in a β-aminopropionitrile (BAPN)-induced AAD mouse model through a series of behavioral assays. Drug-target Mendelian randomization analysis was conducted to identify candidate genes implicated in this association. Expression levels of PRDX6 were examined in brain tissues from Alzheimer's disease patients using datasets from the Gene Expression Omnibus (GEO), as well as in aortic tissues and blood samples obtained from both AAD patients and AAD model mice. Correlative analyses between PRDX6 and pro-inflammatory cytokines (IL-1β and TNF-α) were performed in mouse hippocampal tissues of the mouse model. Additionally, in vitro experiments employing SH-SY5Y cells were carried out to investigate the functional role of PRDX6 in modulating synaptic protein expression and inflammatory responses.

RESULTS

Competing risk regression analysis indicated that AAD is significantly associated with an increased incidence of cognitive impairment. Behavioral testing revealed that AAD model mice exhibited deficits in cognitive performance. Mendelian randomization prioritized PRDX6 was prioritized as a candidate gene of interest. Elevated PRDX6 expression was observed in brain tissues from Alzheimer's disease patients. Both AAD patients and AAD model mice demonstrated markedly increased PRDX6 levels in aortic tissues and circulating blood; notably, PRDX6 expression was also upregulated in the hippocampus of AAD mice. In the hippocampus, PRDX6 expression positively correlated with levels of IL-1β and TNF-α expression in AAD mice. In SH-SY5Y cells, silencing of PRDX6 resulted in increased expression of synaptic proteins, reduced pro-inflammatory cytokine production, and decreased apoptosis, whereas overexpression of PRDX6 elicited inverse effects.

CONCLUSIONS

The present findings establish a significant association between AAD and heightened risk of cognitive impairment. PRDX6 has been identified as a potential mediator in this relationship, and PRDX6-related neuroinflammation is proposed as a plausible mechanistic pathway linking AAD to cognitive dysfunction.