Hyperbaric Oxygen Therapy Reversed Cognitive Deficits in a Murine Model of Alzheimer's Disease

Abstract

Lack of medications or procedures available for reversing or modifying the progression of Alzheimer's disease (AD) has led to heightened search for alternatives. This is in the face of over 400 failed clinical trials that have targeted specific pathways in the pathophysiology of the disease including β-amyloid, tau and inflammation. Based on these failures and the complexity of AD, examining alternative treatments that target several disease-related pathways in parallel is of utmost importance. Oxidative stress and neuroinflammation have been identified as major factors involved in the pathogenesis of AD, therefore a treatment that has the potential to reduce these two factors could decrease AD pathologies and improve brain function. Hyperbaric oxygen therapy (HBOT) has been used for the past 50 years for decompression sickness, thermal burns, and wound healing among others. Recently, HBOT has been shown as a promising treatment for conditions such as traumatic brain injury and stroke, and improved cognitive function while reducing inflammation and plaque deposition in the 3xTg mouse model of AD. In a model of atherosclerosis, HBOT reduced systemic inflammation and induced antioxidant enzymes. More recently, HBOT treatment improved cognitive impairment in 42 AD patients. The objective of this experiment was to further characterize and optimize the use of HBOT as a novel avenue to treat AD. It was hypothesized that HBOT will reverse cognitive impairments associated with AD by reducing neuroinflammation and boosting antioxidant defenses. Male and female 5xFAD mice together with age-matched control (non-carriers) were divided into 4 groups: control-HBOT, control +HBOT, 5xFAD-HBOT and 5xFAD+HBOT. At 9 months, HBOT was started (consisting of increasing the O2 pressure to 2ATM and maintaining it for 90 min). A battery of behavioral tests assessing motor and cognitive function was started 1 month into the treatment. The 5xFAD mice exhibited poorer spatial and associative learning and impaired cognitive flexibility. These deficits were mostly restored by HBOT, especially in females on all three tests. Female 5xFAD mice exhibited hypoactivity, which was reversed to normal activity levels by HBOT. While these results are preliminary, they do support HBOT as a viable option for managing AD. It sets the stage to look into the redox status and molecular components/pathway of parts of the brain that are adversely affected in AD. Identification of these targets and pathway could lead to potential development of novel therapeutic approaches in AD.