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

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.

A Proteotranscriptomic-Based Computational Drug-Repositioning Method for Alzheimer’s Disease

“…Iproniazid, another MAO inhibitor, is used as an antidepressant drug (Yáñez et al, 2012). Several mechanisms have been proposed to account for involvement of MAO in AD pathology such as cognitive dysfunction via destroying cholinergic neurons and the formation of Aß aggregation or NFTs (Thomas, 2000;Huang et al, 2012;Mousseau and Baker, 2012;Cai, 2014;Quartey et al, 2018). This is in line with the recent study reporting that selegiline suppressed GABA production from reactive astrocytes, and restores the synaptic plasticity, and learning and memory function in the AD model mice (Park et al, 2019).…”

“…In another way, bupivacaine may act on AMP-activated protein kinase (AMPK), and subsequently activate the downstream of AMPK (Huang et al, 2014). Selegiline and iproniazid are inhibitors of monamine oxidase inhibitors (MAO) that are known to be implicated in the AD pathology (Thomas, 2000;Huang et al, 2012;Quartey et al, 2018) (Figure 5B). In this context, this approach can repurpose potential anti-AD drug candidates that may be further investigated.…”

Neuroprotective actions of leptin facilitated through balancing mitochondrial morphology and improving mitochondrial function

“…In vitro studies demonstrate that Aβ peptides (1-42, 25-35) damage mitochondrial membrane potential (ΔΨm), increase ROS and cause abnormal mitochondrial fragmentation in several cell lines and also in primary neuronal cultures (Barsoum et al, 2006;Cha et al, 2012). A recent study on Alzheimer's disease brains revealed a complex dysregulation of the activities of specific mitochondrial enzymes, monoamine oxidases A and B (MAO A and B) and further confirmed that mRNA, protein and activity of the MAOs varied independently (Quartey et al, 2018). These observations suggest a central role for mitochondria in neurodegeneration that warrants investigation.…”

“…Because of the production of hydrogen peroxide and induced oxidative stress, excessive MAO activity is regarded as a risk factor in AD (Quartey et al, 2018). Indeed, inhibition of MAO has been proposed as a treatment target in AD (Hroch et al, 2017; Naoi & Maruyama, 2010).…”

Relationships between Mitochondrial Dysfunction and Neurotransmission Failure in Alzheimer’s Disease

“…Abnormal MAO activity promotes the loss of monoamines and mitochondrial peroxidation in AD. The activity of hippocampal MAO was significantly increased in humans carrying ε4 allele of apolipoprotein E and in experimental mouse models of AD [186][187][188]. This enhanced MAO activity not only causes insufficient monoamines for neurotransmission, but also induces significantly higher levels of peroxidative stress in monoaminergic neurones via H2O2 production.…”