S-9-PAHSA Attenuates Aβ Accumulation and Improves Cognitive Deficits by Promoting Mitochondrial Autophagy in 5xFAD Mice.

Alzheimer's disease (AD) is a prevalent neurodegenerative disorder characterized by significant cognitive impairment and predominantly affects the elderly. With no effective cure available, research continues to explore novel therapeutic and preventive strategies. Recently, palmitic acid-hydroxystearic acids (PAHSAs), especially their stereochemistry S-configuration, have shown potential as a dietary supplement with anti-inflammatory and anti-diabetic properties. We previously found that one of the PAHSAs, 9-PAHSA, could improve cognitive impairment in the high-fat-diet mice, however, whether it has an equal effect on AD-like mice remains unclear. Since mitochondrial dysfunction is recognized as a significant pathological feature of AD, with impaired mitophagy leading to the accumulation of dysfunctional mitochondria, thus exacerbating disease progression, in this study, we evaluated the effects of the chiral isomer of 9-PAHSA, S-9-PAHSA, on cognitive dysfunction and mitochondrial dysfunction in 5xFAD mice. Three-month-old mice were treated with S-9-PAHSA 30 mg/kg in their drinking water for 3 months. Behavioral studies were conducted using the Morris Water Maze (MWM) and Y-maze tests, followed by assessments of amyloid-beta (Aβ) plaque deposition, neuronal apoptosis, and mitochondrial function. We found that S-9-PAHSA significantly enhanced spatial learning and memory abilities, reduced amyloid plaque deposition, decreased neuronal apoptosis, and improved mitochondrial homeostasis and autophagy in 5xFAD mice. These findings suggest that S-9-PAHSA holds promise as a supplementary preventive and therapeutic strategy for AD treatment.