Hyperbaric Oxygen Treatment improved Cognitive deficits in a mouse model of Alzheimer's Disease
0000-0001-6380-3845 (Davis, Delaney)
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Purpose: Alzheimer's disease (AD) is an economic burden affecting 40 million people worldwide and projected to increase to 120 million by the year 2050. Current approved treatments of AD only manage symptoms, involving anti-cholinesterase or NMDA antagonist. Seeking out new therapeutics and interventions that can reverse and alleviate the devastating effects of this disease has become paramount. Though a complex disease, there are major factors such as hypoxia, oxidative stress, and neuroinflammation that have been heavily involved in the pathogenesis of AD. Interventions that can reduce these two factors would likely reverse the progression of the disease. Hyperbaric Oxygen Therapy (HBOT), which has been used for the past 50 years for thermal burns, decompression sickness among other conditions, seems promising for neurological conditions such as traumatic brain injury and stroke. It has been shown to reduce inflammation and hypoxia. At the center of AD controversy also, is the relative vulnerability of the different sexes to AD. Whereas most studies in the US show no difference in incidence, studies in Europe have demonstrated a higher risk in women than men. On the contrary another study in United Kingdom reported men are at a higher risk. Thus, it has become more important to use both sexes in any study that seeks a successful treatment. Therefore, our aim was to explore whether HBOT can improve cognition in both male and female 5xFAD (AD model) mice. Methods: A total of 132 male and female 5xFAD and wildtype (WT) mice were randomly assigned to one of four experimental groups consisting of WT-HBOT, WT+HBOT, 5xFAD-HBOT and 5xFAD+HBOT. HBOT (O2 pressure at 2.4 ATA maintained for 90 min) daily (5 days/week) was started at 9-10 months and continued until the mice were euthanized at 12-13 months. Morris water maze test for spatial learning and memory, active avoidance T maze test for cognitive flexibility and fear conditioning test for associative learning were carried out at 1 month into the treatment with HBOT. Results: HBOT improved spatial learning and memory deficits in 5xFAD males but not in females. However, cognitive flexibility impairments were reversed with HBOT in 5xFAD females but not males. Also, HBOT improved associative learning in 5xFAD females, a deficit which was absent in males. Conclusion: This work does support HBOT as a viable option for reversing cognitive impairment associated with an AD phenotype with some sex differences depending on cognitive domain. Future work will seek to evaluate the mechanisms of action of HBOT including the possible involvement of epigenetics and sex differences, to help bring some clarity to the equivocal vulnerability of males and females to AD.