Treatment of Alzheimer’s disease (AD) has been limited to managing of symptoms or anti-amyloid therapy with limited results and uncertainty. Seeking out new therapies that can reverse the effects of this devastating disease is important. Hyperbaric oxygen (HBO) therapy could be such a candidate as it has been shown to improve brain function in certain neurological conditions. Furthermore, the role sex plays in the vulnerability/resilience to AD remains equivocal. An understanding of what makes one sex more vulnerable to AD could unveil new pathways for therapy development. In this study, we investigated the effects of HBO on cognitive, motor, and affective function in a mouse model of AD (5xFAD) and assessed protein oxidation in peripheral tissues as a safety indicator. The motor and cognitive abilities of 5xFAD mice were significantly impaired. HBO therapy improved cognitive flexibility and associative learning of 5xFAD females but not males, but HBO had no effect other aspects of cognition. HBO also reversed AD-related declines in balance but had no impact on gait and anxiety-like behavior. HBO did not affect body weights or oxidative stress in peripheral tissues. Our study provides further support for HBO therapy as a potential treatment for AD and emphasizes the importance of considering sex as a biological variable in therapeutic development. Further investigations into the underlying mechanisms of HBO’s sex-specific responses are warranted, as well as optimizing treatment protocols for maximum benefits.

阿尔茨海默氏病（AD）的治疗仅限于控制症状或抗淀粉样蛋白治疗，效果有限且不确定。寻找可以逆转这种毁灭性疾病影响的新疗法非常重要。高压氧（HBO）疗法可能是这样的候选者，因为它已被证明可以改善某些神经系统疾病的大脑功能。此外，性在AD的脆弱性/恢复力中所扮演的角色仍然是模棱两可的。了解是什么让一种性别更容易患阿尔茨海默病，可能会为治疗开发提供新的途径。在这项研究中，我们研究了 HBO 对 AD 小鼠模型 (5xFAD) 认知、运动和情感功能的影响，并评估外周组织中的蛋白质氧化作为安全指标。5xFAD 小鼠的运动和认知能力显着受损。HBO 治疗改善了 5xFAD 女性的认知灵活性和联想学习，但对男性没有影响，但 HBO 对认知的其他方面没有影响。HBO 还逆转了 AD 相关的平衡能力下降，但对步态和焦虑样行为没有影响。HBO 不影响体重或外周组织的氧化应激。我们的研究进一步支持 HBO 疗法作为 AD 的潜在治疗方法，并强调在治疗开发中将性别视为生物学变量的重要性。有必要进一步研究 HBO 性别特异性反应的潜在机制，并优化治疗方案以获得最大益处。