Hyperbaric oxygen therapy ameliorates Alzheimer's disease pathology by restoration of mitophagy and suppressing neuroinflammation in 5xFAD mice.

Alzheimer's disease (AD) is characterized by amyloid-β (Aβ) accumulation, synaptic dysfunction, and chronic neuroinflammation. Here, we demonstrate that hyperbaric oxygen therapy (HBOT) has multiple therapeutic effects in 5xFAD transgenic mice. HBOT significantly improved cognitive function. Treated mice increasingly moved to the center of the open field in Y-maze tests and preferred a new arm. Longitudinal ¹⁸F-AV-45 PET-MR scans showed progressive reduction in amyloid tracer uptake, which was corroborated by histologically verified reduced plaque burden and upregulation of LRP1, a key Aβ clearance transporter. HBOT preserved neuronal density and enhanced synaptic proteins. Mechanistically, HBOT promoted mitochondrial quality control by upregulating PINK1 and parkin expression, enhancing autophagosome formation, and modulating mitophagy-associated pathways. The transition of microglia to a surveillance phenotype was reflected in decreased soma area and increased branching. The coordinated improvement in amyloid clearance, mitochondrial quality control and synaptic maintenance, and modulation of neuroinflammation suggest that the ability of HBOT to simultaneously act on multiple pathological cascades-in combination with its noninvasive nature and favorable safety profile-makes it a uniquely promising therapeutic strategy. Furthermore, these results suggest that HBOT may be particularly effective at an early stage of the disease. These studies will be critical in establishing the clinical applicability of HBOT in the treatment of Alzheimer's disease.