Cardiac-derived extracellular vesicles carrying miR-4433b-3p accelerate cognitive decline and brain aging by suppressing TP53INP2-mediated neuronal autophagy in mice.

Qian Cheng, Zhikang Cui, Shuyi Yu, Guixia Li, Hang Chen, Qian Yu, Jialin Han, Shuang Wu, Yan Jin, Yunshan Wang, Ming Li, Zhiming Lu

Department of Clinical Laboratory, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China.Department of Clinical Laboratory, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China. · pubmed

Paper

Abstract

Brain aging is not an independent process, yet how systemic aging drives neural decline remains unclear. Here, we identified a circulating miR-4433b-3p, packaged within extracellular vesicles (EVs), as a trans-organ effector bridging cardiac aging with central nervous system (CNS) decline. Small RNA sequencing and human cohort validation revealed selective enrichment of miR-4433b-3p in aged plasma EVs (Op-EVs), correlating with blood biomarkers of brain aging. Source tracing in mice identified the aged heart as the major origin of miR-4433b-3p-laden EVs. Functionally, aged cardiac EVs (Oc-EVs) accumulated in the hippocampus, impaired memory and induced neuronal senescence. Mechanistically, miR-4433b-3p suppressed TP53INP2, a facilitator of autophagic flux, leading to disrupted autophagosome maturation. Restoring TP53INP2 or inhibiting miR-4433b-3p rescued neuronal autophagy and improved cognition. Collectively, these findings uncover a heart-brain axis by EV-mediated miRNA signaling, positioning cardiac EV-miR-4433b-3p as a circulating biomarker and potential therapeutic target for age-related cognitive decline.

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Research summary

The paper claims that cardiac-derived extracellular vesicles carrying miR-4433b-3p accelerate cognitive decline by suppressing neuronal autophagy. This research is relevant as it explores the mechanisms linking cardiac aging to cognitive decline, addressing potential root causes of age-related cognitive impairment rather than merely treating symptoms.

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