Ovariectomy Influences Cognition and Markers of Alzheimer’s Disease

Article type: Research Article

Authors: Agca, Cansu^a | Klakotskaia, Diana^b | Stopa, Edward G.^{c; †} | Schachtman, Todd R.^b | Agca, Yuksel^{a; *}

Affiliations: [a] Department of Veterinary Pathobiology, College of Veterinary Medicine, University of Missouri, Columbia, MO, USA | [b] Department of Psychological Sciences, University of Missouri, Columbia, MO, USA | [c] Departments of Pathology and Neurosurgery, Brown University, Rhode Island Hospital, Providence, RI, USA

Correspondence: [*] Correspondence to: Yuksel Agca, DVM, MS, PhD, Associate Professor, Department of Veterinary Pathobiology, College of Veterinary Medicine, University of Missouri, Columbia, MO 65211, USA. E-mail: [email protected].

Note: [†] Deceased.

Abstract: Alzheimer’s disease (AD) is one of the most devastating and costly diseases, and prevalence of AD increases with age. Furthermore, females are twice as likely to suffer from AD compared to males. The cessation of reproductive steroid hormone production during menopause is hypothesized to cause this difference. Two rodent AD models, APP21 and APP+PS1, and wild type (WT) rats underwent an ovariectomy or sham surgery. Changes in learning and memory, brain histology, amyloid-β (Aβ) deposition, levels of mRNAs involved in Aβ production and clearance, and synaptic and cognitive function were determined. Barnes maze results showed that regardless of ovariectomy status, APP+PS1 rats learned slower and had poor memory retention. Ovariectomy caused learning impairment only in the APP21 rats. High levels of Aβ42 and very low levels of Aβ40 were observed in the brain cortices of APP+PS1 rats indicating limited endogenous PS1. The APP+PS1 rats had 43-fold greater formic acid soluble Aβ42 than Aβ40 at 17 months. Furthermore, levels of formic acid soluble Aβ42 increased 57-fold in ovariectomized APP+PS1 rats between 12 and 17 months of age. The mRNA encoding Grin1 significantly decreased due to ovariectomy whereas levels of Bace1, Chat, and Prkcb all decreased with age. The expression levels of mRNAs involved in Aβ degradation and AβPP cleavage (Neprilysin, Ide, Adam9, and Psenen) were found to be highly correlated with each other as well as hippocampal Aβ deposition. Taken together, these results indicate that both ovariectomy and genotype influence AD markers in a complex manner.

Keywords: Alzheimer’s disease, amyloid-β , estrogen, gene expression, ovarian hormones, ovariectomy, progesterone, rat, transgenic

DOI: 10.3233/JAD-190935

Journal: Journal of Alzheimer's Disease, vol. 73, no. 2, pp. 529-541, 2020