Alzheimer Disease and Selected Risk Factors Disrupt a Co-regulation of Monoamine Oxidase-A/B in the Hippocampus, but Not in the Cortex.

Maa O Quartey,Paul R Pennington,Paula C Klassen,Jennifer N K Nyarko,Darrell D Mousseau,Glen B Baker,Ryan M Heistad

doi:10.3389/fnins.2018.00419

Maa O Quartey, Paul R Pennington + Show 5 more

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https://doi.org/10.3389/fnins.2018.00419

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Abstract

Monoamine oxidase-A (MAO-A) and MAO-B have both been implicated in the pathology of Alzheimer disease (AD). We examined 60 autopsied control and AD donor brain samples to determine how well MAO function aligned with two major risk factors for AD, namely sex and APOE ε4 status. MAO-A activity was increased in AD cortical, but not hippocampal, samples. In contrast, MAO-B activity was increased in both regions (with a strong input from female donors) whether sample means were compared based on: (a) diagnosis alone; (b) diagnosis-by-APOE ε4 status (i.e., carriers vs. non-carriers of the ε4 allele); or (c) APOE ε4 status alone (i.e., ignoring ‘diagnosis’ as a variable). Sample means strictly based on the donor’s sex did not reveal any difference in either MAO-A or MAO-B activity. Unexpectedly, we found that cortical MAO-A and MAO-B activities were highly correlated in both males and females (if focussing strictly on the donor’s sex), while in the hippocampus, any correlation was lost in female samples. Stratifying for sex-by-APOE ε4 status revealed a strong correlation between cortical MAO-A and MAO-B activities in both non-carriers and carriers of the allele, but any correlation in hippocampal samples was lost in carriers of the allele. A diagnosis of AD disrupted the correlation between MAO-A and MAO-B activities in the hippocampus, but not the cortex. We observed a novel region-dependent co-regulation of MAO-A and MAO-B mRNAs (but not proteins), while a lack of correlation between MAO activities and the respective proteins corroborated previous reports. Overexpression of human APOE4 increased MAO activity (but not mRNA/protein) in C6 and in HT-22 cell cultures. We identified a novel co-regulation of MAO-A and MAO-B activities that is spared from any influence of risk factors for AD or AD itself in the cortex, but vulnerable to these same factors in the hippocampus. Sex- and region-dependent abilities to buffer influences on brain MAO activities could have significant bearing on ambiguous outcomes when monoaminergic systems are targeted in clinical populations.

Highlights

The two isoforms of monoamine oxidase [amine: oxygen oxidoreductase, EC 1.4.3.4, monoamine oxidase (MAO)], i.e., Monoamine oxidase-A (MAO-A) and MAO-B, are expressed primarily on the mitochondria
Mean platelet MAOB activity has been shown to correlate with MAO-B mRNA and protein expression (Zellner et al, 2012) and to increase in female Alzheimer disease (AD) patients (Robinson et al, 1971; Veral et al, 1997), while MAO-A or MAO-B activities tend to correlate with the respective proteins or binding densities (reviewed in (Tong et al, 2013))
While we could not fully characterize the role of this co-regulation in the male and female brain, the findings do provide insight into the role of MAOs – and the monoaminergic neurotransmitters that they regulate– and support sex– and genetic-specific responses to risk of AD and the pathology associated with disease progression

Summary

Introduction

The two isoforms of monoamine oxidase [amine: oxygen oxidoreductase (deaminating) (flavin containing), EC 1.4.3.4, monoamine oxidase (MAO)], i.e., MAO-A and MAO-B, are expressed primarily on the mitochondria. Changes in levels of the MAO-mediated acid metabolites of serotonin and dopamine – i.e., 5-hydroxyindole-3-acetic acid (5-HIAA) and homovanillic acid (HVA), respectively– have long been associated with cognitive deficits and dementia (Gottfries et al, 1969a,b; Nazarali and Reynolds, 1992; Vermeiren et al, 2015) and are observed in diverse mouse models of AD-related pathology (Ash et al, 2010; Wei et al, 2012). Levels of monoamine acid metabolites have been positively correlated with cerebrospinal levels of Aβ (Stuerenburg et al, 2004), while MAO-B-positive astrocytes are detected in the vicinity of amyloid plaques, a hallmark of AD neuropathology (Saura et al, 1994) This latter association has been re-confirmed recently using two-photon imaging in the 5xFAD mouse model of AD (Kim et al, 2016). Reversible inhibitors of MAO-A, such as moclobemide, have shown modest results in elderly individuals, including those presenting with cognitive deficits (Rosenzweig et al, 1998; Gareri et al, 2000), whereas inhibitors of MAO-B, such as l-deprenyl, might provide benefit in the early stages of clinical neurodegenerative diseases, such as Parkinson’s disease (Magyar et al, 2004; Youdim et al, 2006) and mild AD-type dementia (Riederer et al, 2004)

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