Exosomal miR‐532‐5p induced by long‐term exercise rescues blood–brain barrier function in 5XFAD mice via downregulation of EPHA4

Abstract

The breakdown of the blood–brain barrier, which develops early in Alzheimer's disease (AD), contributes to cognitive impairment. Exercise not only reduces the risk factors for AD but also confers direct protection against cognitive decline. However, the exact molecular mechanisms remain elusive, particularly whether exercise can liberate the function of the blood–brain barrier. Here, we demonstrate that long‐term exercise promotes the clearance of brain amyloid‐β by improving the function of the blood–brain barrier in 5XFAD mice. Significantly, treating primary brain pericytes or endothelial cells with exosomes isolated from the brain of exercised 5XFAD mice improves cell proliferation and upregulates PDGFRβ, ZO‐1, and claudin‐5. Moreover, exosomes isolated from exercised mice exhibit significant changes in miR‐532‐5p. Administration or transfection of miR‐532‐5p to sedentary mice or primary brain pericytes and endothelial cells reproduces the improvement of blood–brain barrier function. Exosomal miR‐532‐5p targets EPHA4, and accordingly, expression of EphA4 is decreased in exercised mice and miR‐532‐5p overexpressed mice. A specific siRNA targeting EPHA4 recapitulates the effects on blood–brain barrier‐associated cells observed in exercised 5XFAD mice. Overall, our findings suggest that exosomes released by the brain contain a specific miRNA that is altered by exercise and has an impact on blood–brain barrier function in AD.

Micro Trojan horses: Engineering extracellular vesicles crossing biological barriers for drug delivery

“…Recent research indicates that mitochondrial‐enriched endothelial cell‐derived exosomes can restore TJ integrity by increasing ATP levels and restoring mitochondrial function 132 . In addition, exercise has been demonstrated to improve the BBB's structure and function by promoting the expression of TJ‐related proteins, inducing endothelial cell proliferation, and altering the types of miRNAs in exosomes in peripheral blood 133 …”

“…132 In addition, exercise has been demonstrated to improve the BBB's structure and function by promoting the expression of TJ-related proteins, inducing endothelial cell proliferation, and altering the types of miRNAs in exosomes in peripheral blood. 133 In certain pathological conditions, EVs have been observed to potentially contribute to the breakdown of the BBB, and facilitate brain inflammation and tumor metastasis. [134][135][136] Research indicates that plasma-derived EVs from pediatric patients with OSA may impair the TJs of the BBB, resulting in increased permeability by disrupting ZO-1 continuity.…”

Leveraging the glymphatic and meningeal lymphatic systems as therapeutic strategies in Alzheimer’s disease: an updated overview of nonpharmacological therapies

“…The physical exercise-induced improvements in glymphatic function have been concentrated on the recovery of the aging-associated reduction of polarized AQP4 [ 32 ]. Nevertheless, the neuroprotective effects of physical exercise in dementia have also been associated with sleep regulation [ 134 ] and improvement of vascular function [ 98 , 135 ]. Aerobic exercise has been especially effective in reducing sleep medication intake and sleep latency in the elderly and patients with AD [ 134 ].…”

“…Since the prevalence of sleep disorders and physical inactivity among AD subjects is remarkably high [ 19 ], the beneficial effects of physical exercise on improving sleep could also contribute to the glymphatic function. Moreover, animal studies have shown that long-term physical exercise protects against neurovascular deterioration by preventing aging-associated astrocyte dysfunction, pericyte injury, and basal lamina impairments [ 98 , 135 ]. Of note, Morland and colleagues [ 136 ] demonstrated that the physical exercise angiogenic properties are dependent on the activation of the lactate receptor, hydroxycarboxylic acid receptor 1 (HCAR1), which is highly expressed in pericyte-like cells surrounding penetrating arterioles.…”

Biomarker profiling to determine clinical impact of microRNAs in cognitive disorders

“…Other specific links between miRNAs and AD include miR-29c-3p, miR-193b, miR-132, miR-103, and miR-181c regulating Aβ activity; miR-181c, miR-31, miR-93 20 , and miR-146 21 modulating microglial inflammatory response in the CNS; as well as miR-125b 22 , miR-26b, miR-483-5p, and miR-502-3p influencing tau protein activity and NFT formation 23 . Additionally, miR-532-5p targets EPHA4 to ameliorate BBB damage 24 , while miR-126 targets EFHD2 to promote the formation and modulation of contextual fear memory in patients with AD 25 . The available data all point to the importance of miRNAs in influencing AD onset and symptoms.…”