Congruency of exosome-mediated blood-brain barrier dysfunction by activation of Na/K-ATPase in obstructive sleep apnea and Alzheimer's disease.

Obstructive sleep apnea (OSA) and Alzheimer's disease (AD) are highly prevalent chronic disorders that share several pathological features, including oxidative stress, inflammation, vascular dysfunction, and cognitive impairment. Although epidemiological studies have demonstrated a strong association between OSA and an increased risk of AD, the mechanisms linking these disorders remain poorly understood. We hypothesized that circulating plasma exosomes from patients with OSA or AD disrupt blood-brain barrier (BBB) integrity through activation of Na⁺/K⁺-ATPase signaling. Plasma exosomes were isolated from adult male patients with OSA or AD (n = 10/group) and applied to naïve human brain microvascular endothelial cells (hCMEC/D3). BBB integrity was continuously monitored using electric cell-substrate impedance sensing (ECIS) in the presence or absence of the Na⁺/K⁺-ATPase signaling inhibitor pNaKtide (0-2.0 µM). Exosomes derived from both OSA and AD patients significantly impaired endothelial barrier function, indicating that circulating extracellular vesicles carry bioactive cargo capable of disrupting BBB integrity. Pharmacological inhibition of Na⁺/K⁺-ATPase signaling with pNaKtide significantly restored barrier function at concentrations of 1.0 and 2.0 µM, although the degree of protection differed between the OSA- and AD-derived exosomes, suggesting disease-specific mechanisms of endothelial injury. These findings identify Na⁺/K⁺-ATPase signaling as a key mediator of exosome-induced BBB dysfunction and provide mechanistic evidence linking circulating extracellular vesicles to neurovascular injury in both OSA and AD. Collectively, our results suggest that plasma-derived exosomes contribute to BBB disruption and highlight Na⁺/K⁺-ATPase signaling as a promising therapeutic target for preventing or attenuating neurovascular dysfunction associated with OSA and AD.