Research Paper Volume 13, Issue 9 pp 12817—12832

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

Qiujian Yu1, *, , Xiaoqin Cheng2, *, ,

  • 1 Department of Neurology, First Affiliated Hospital of Kunming Medical University, Kunming 650000, China
  • 2 Department of Neurology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
* Equal contribution

Received: November 11, 2020       Accepted: March 29, 2021       Published: May 11, 2021      

https://doi.org/10.18632/aging.202949
How to Cite

Copyright: © 2021 Yu and Cheng. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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.

Abbreviations

AD: Alzheimer’s disease; AMPK: AMP-activated protein kinase; ACC: acetyl CoA carboxylase; CPT1: carnitine palmitoyl transferase 1; DHA: Docosahexaenoic acid; EPA: eicosapentaenoic acid; DPA: docosapentaenoic acid; HU: Hydroxyurea.