WWOX is a recently defined risk factor for Alzheimer’s disease (AD). Functional deficiency or downregulation of WWOX protein may lead to slow protein aggregation in the brain that contributes to the pathogenesis of AD. Previously, we demonstrated that WWOX deficiency initiates the aggregation of TRAPPC6AΔ, TIAF1, tau and Aβ. TRAPPC6AΔ aggregates or plaques are found in the brain cortex and hippocampus in middle-aged healthy individuals (aged 40 to 70) and old AD patients (70-100 years old). Here, we determined that HAson8 (hyaluronan sonicated for 8 hr) significantly retarded AD progression and restored memory loss in triple-transgenic mouse (3×Tg) model for AD, as determined by novel object recognition test (ORT) and Morris water maze for hippocampus-dependent, non-spatial and spatial learning and memory. By immunohistochemistry, HAson8 significantly suppressed the aggregation of Aβ and pT181-Tau, and reduced the levels of inflammatory microglia and astrocytes in 12-month-old 3xTg mouse hippocampi. Also, HAson8 significantly suppressed the expression of AD-promoting pS14-WWOX in the hippocampi. HAson8 significantly upregulated neural stem cells, expressing Sox2 and parvalbumin in the subventricular zone and hippocampi. Mechanistically, HAson8 activated Hyal-2+ Z cells, and that transfer of the activated Z cells to recipient 3xTg enabled these mice to restore memory loss at month 9. Finally, HAson8 altered the ratio of Firmicutes and Bacteroidetes bacteria in the gut, which favors the retardation of AD progression in 3xTg mice. Together, HAson8 is effective in inhibiting AD progression in 3xTg mice via suppression of inflammatory glia cells, upregulation of Z cells and neural stem cells, and reducing AD-promoting gut bacteria.
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Ministry of Science and Technology, Taiwan and National Health Research Institute, Taiwan
