Hydroxyurea-induced membrane fluidity decreasing as a characterization of neuronal membrane aging in Alzheimer’s disease

Abstract

Aging is one of the significant risk factors for Alzheimer’s disease (AD). Therefore, this study aimed to propose a new hypothesis “membrane aging” as a critical pathogenesis of AD. The concept of “membrane aging” was reviewed, and the possible mechanisms of membrane aging as the primary culprit of AD were clarified. To further prove this hypothesis, a hydroxyurea-induced “membrane aging” model was established in vitro and in vivo . First, neuronal aging was validated by immunocytochemistry with age-related markers, and membrane aging phenotypes were confirmed. The alterations of membrane fluidity within APP/PS1 mice were re-proved by intracerebroventricular injection of hydroxyurea. Decreased membrane fluidity was found in vitro and in vivo , accompanied by increased total cholesterol concentration in neurons but decreased cholesterol levels within membrane fractions. The Aβ level increased considerably after hydroxyurea treatment both in vitro and in vivo . DHA co-treatment ameliorated membrane aging phenotypes and Aβ aggregation. The study revealed the AMP-activated protein kinase/acetyl CoA carboxylase/carnitine palmitoyl transferase 1 pathway involved in membrane aging processes. These results strongly supported the idea that membrane aging was a pathogenesis of AD and might serve as a new therapeutic target for AD.

Dynamic Progress in Technological Advances to Study Lipids in Aging: Challenges and Future Directions

“…Also, altered membrane lipid composition, and more specifically, decreased membrane fluidity, have been implicated in aging. For instance, in rat primary cortical neurons treated with hydroxyurea to provoke senescent-like alterations, changes in membrane lipid composition led to decreased membrane fluidity ( Yu and Cheng, 2021 ). In another study, using both ensemble and single-molecule fluorescence imaging techniques, decreased membrane fluidity and increased membrane hydrophobicity were measured in senescent cells ( Wi et al, 2021 ).…”