Estrogen deficiency exacerbates learning and memory deficits associated with glucose metabolism disorder in APP/PS1 double transgenic female mice

Min Luo; Qinghua Zeng; Kai Jiang; Yueyang Zhao; Zhimin Long; Yexiang Du; Kejian Wang; Guiqiong He

doi:10.1016/j.gendis.2021.01.007

Estrogen deficiency exacerbates learning and memory deficits associated with glucose metabolism disorder in APP/PS1 double transgenic female mice

Genes Dis. 2021 Feb 16;9(5):1315-1331. doi: 10.1016/j.gendis.2021.01.007. eCollection 2022 Sep.

Authors

Min Luo^{1

2}, Qinghua Zeng^{1

3}, Kai Jiang⁴, Yueyang Zhao¹, Zhimin Long^{1

3}, Yexiang Du¹, Kejian Wang^{1

3}, Guiqiong He^{1

3}

Affiliations

¹ Chongqing Key Laboratory of Neurobiology, Chongqing Medical University, Chongqing 400016, PR China.
² Department of Pathology, Suining Municipal Hospital of TCM, Suining, Sichuan 629000, PR China.
³ Department of Anatomy, Chongqing Medical University, Chongqing 400016, PR China.
⁴ Department of Gastroenterology, Suining Central Hospital, Suining, Sichuan 629000, PR China.

Abstract

Alterations in glucose metabolism occur in the brain in the early stage of Alzheimer's disease (AD), and menopausal women have more severe metabolic dysfunction and are more prone to dementia than men. Although estrogen deficiency-induced changes in glucose metabolism have been previously studied in animal models, their molecular mechanisms in AD remain elusive. To investigate this issue, double transgenic (APP/PS1) female mice were subjected to bilateral ovariectomy at 3 months of age and were sacrificed 1 week, 1 month and 3 months after surgery to simulate early, middle and late postmenopause, respectively. Our analysis demonstrated that estrogen deficiency exacerbates learning and memory deficits in this mouse model of postmenopause. Estrogen deficiency impairs the function of mitochondria in glucose metabolism. It is possible that the occurrence of AD is associated with the aberrant mitochondrial ERβ-mediated IGF-1/IGF-1R/GSK-3β signaling pathway. In this study, we established a potential mechanism for the increased risk of AD in postmenopausal women and proposed a therapeutic target for AD due to postmenopause.

Keywords: Alzheimer's disease; Estrogen deficiency; GSK-3β; Glucose metabolism disorder; IGF-1; Mitochondria.