Reduced Hippocampal and Anterior Cingulate Expression of Antioxidant Enzymes and Membrane Progesterone Receptors in Alzheimer’s Disease with Depression

Article type: Research Article

Authors: Luo, Wendy^a | Pryzbyl, Katherine J.^a | Bigio, Eileen H.^b | Weintraub, Sandra^{a; b} | Mesulam, M.-Marsel^b | Redei, Eva E.^{a; *}

Affiliations: [a] Department of Psychiatry and Behavioral Sciences, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA | [b] Mesulam Center for Cognitive Neurology and Alzheimer’s Disease, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA

Correspondence: [*] Correspondence to: Eva E. Redei, PhD, Department of Psychiatry and Behavioral Sciences, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA. Tel.: +1 312 908 1791; E-mail: e-redei@northwestern.edu.

Abstract: Background:Major depressive disorder (MDD) is a risk factor for dementia including that caused by Alzheimer’s disease (AD). Both MDD and AD have a higher prevalence in women than men, and estrogen-related processes have been implicated in this sex difference. Objective:To identify if enhanced oxidative stress and decreased expression of the memory enhancer insulin-like growth factor 2 (IGF2), each implicated separately in MDD and AD, are exaggerated in individuals with both AD and MDD compared to those with AD. Methods:Expression of target genes are determined by qPCR in postmortem hippocampus (Hip) and anterior cingulate cortex (ACC) of individuals with dementia and autopsy confirmed AD and those of AD+MDD. Results:Transcript levels of the antioxidant enzymes catalase (CAT) and superoxide dismutase 1 (SOD1), as well as IGF2 and its receptor (IGF2R) were significantly lower in the Hip and ACC of individuals with both AD and MDD compared to those with AD and no MDD. Expressions of Progestin and AdipoQ Receptor Family Member 7 (PAQR7, alias progesterone receptor alpha, mPRa) and PAQR8 (mPRβ), receptors that bind neurosteroids, were also lower in the Hip and ACC of AD+MDD samples compared to those of AD without MDD. Correlations among these transcripts revealed that estrogen receptor 2 (ESR2) and mPR β are direct or indirect regulators of the expression of the antioxidant enzymes and IGF2R. Conclusion:Reduced levels of antioxidant enzymes, decreased IGF2 expression, and diminished estrogen or membrane progesterone receptor-dependent processes might be more pronounced in the subpopulation of individuals with AD and MDD than without MDD.

Keywords: Antioxidant enzymes, depression, insulin like growth factor 2, membrane progesterone receptor, molecular vulnerability, sex/gender differences

DOI: 10.3233/JAD-220574

Journal: Journal of Alzheimer's Disease, vol. 89, no. 1, pp. 309-321, 2022