Abstract
Vascular dysfunction is entwined with aging and in the pathogenesis of Alzheimer’s disease (AD) and contributes to reduced cerebral blood flow (CBF) and consequently, hypoxia. Hyperbaric oxygen therapy (HBOT) is in clinical use for a wide range of medical conditions. In the current study, we exposed 5XFAD mice, a well-studied AD model that presents impaired cognitive abilities, to HBOT and then investigated the therapeutical effects using two-photon live animal imaging, behavioral tasks, and biochemical and histological analysis. HBOT increased arteriolar luminal diameter and elevated CBF, thus contributing to reduced hypoxia. Furthermore, HBOT reduced amyloid burden by reducing the volume of pre-existing plaques and attenuating the formation of new ones. This was associated with changes in amyloid precursor protein processing, elevated degradation and clearance of Aß protein and improved behavior of 5XFAD mice. Hence, our findings are consistent with the effects of HBOT being mediated partially through a persistent structural change in blood vessels that reduces brain hypoxia. Motivated by these findings, we exposed elderly patients with significant memory loss at baseline to HBOT and observed an increase in CBF and improvement in cognitive performances. This study demonstrates HBOT efficacy in hypoxia-related neurological conditions, particularly in AD and aging.
Highlights
In recent years, it has become clear that vascular dysfunction is entwined in the pathogenesis of Alzheimer’s disease (AD) and cognitive decline during aging [1,2,3]
We found significant reduction in amyloid burden in the hippocampus of HBO-treated 5XFAD mice, as manifested by the reduced percentage of hippocampal area displaying 4G8 immunoreactivity (-54.32%, P=0.0353; Figure 1A, 1B), decreased numbers of plaques (-31.58%, P=0.0217; Figure 1C) and smaller plaque size (-18.94%, P = 0.0125 by Welch's correction; Figure 1D), relative to control 5XFAD mice exposed to normobaric conditions
Following 1 month of Hyperbaric oxygen therapy (HBOT), levels of insoluble Aβ42 were reduced by ~56% (FA fraction, P = 0.0292 by Welch's correction; Figure 1F), while Aβ40 levels were reduced by ~45% (FA fraction, P = 0.0356; Figure 1F) in HBO-treated 5XFAD mice compared with control 5XFAD mice
Summary
It has become clear that vascular dysfunction is entwined in the pathogenesis of Alzheimer’s disease (AD) and cognitive decline during aging [1,2,3]. Cerebral amyloid angiopathy (CAA), the deposition of Aβ peptide in cerebral vessel walls, is the most common vascular pathology in AD [5, 6]. Both AD and CAA are associated with reduced cerebral blood flow (CBF), which precedes the clinical onset of dementia [7,8,9,10] and correlates with the degree of cognitive impairment in AD [1, 11]. Developing treatments that target vascular dysfunction, as well as other AD pathologies, could be a promising avenue for treating the disease and improving cognitive performances in healthy elderly populations suffering from cognitive decline
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