Recent Developments in the Regulation of Monoamine Oxidase Form and Function: Is the Current Model Restricting Our Understanding of the Breadth of Contribution of Monoamine Oxidase to Brain [dys]Function?

Abstract

Historically, much of the focus on monoamine oxidases and their substrates has been in the area of depression and the monoamine neurotransmitters serotonin (5-hydroxytryptamine), noradrenaline, and to a lesser extent, dopamine. With both forms of monoamine oxidase (A and B), the production of hydrogen peroxide as a byproduct of the reaction between the monoamine oxidases and their monoamine substrates has also implicated monoamine oxidase-sensitive events in intrinsic cell death pathways, particularly those centered on oxidative stress and peroxyradical-mediated mechanisms. Consequently, and perhaps not unexpectedly, the inhibition of monoamine oxidase has been considered as adjunctive therapy in neurodegenerative disorders such as Alzheimer's disease and Parkinson's disease, both of which involve a significant oxidative stress component. Yet the literature also provides ambiguities; indeed, not all of the functions of monoamine oxidases are dependent on catalytic activity nor can they all be ascribed to expression levels of the monoamine oxidase protein per se. Recent reports strongly suggest that the functions of monoamine oxidases also rely on posttranslational modifications, epigenetic influences, interactions with other proteins, the cell phenotype and its localization to specific subcellular compartments. These recent developments certainly complicate the issue, yet they need to be duly considered when implicating monoamine oxidases and their inhibitors in both in vitro and in vivo pathological contexts.

Monoamine oxidase B is elevated in Alzheimer disease neurons, is associated with γ-secretase and regulates neuronal amyloid β-peptide levels

“…Here, immunohistochemistry showed staining of MAO-B in neurons as well as glia cells in the frontal cortex, hippocampus and entorhinal cortex, and an increase in the staining intensity was observed both in sporadic and FAD cases as compared to controls. The enhanced MAO-B staining in astrocytes and the presence of such astrocytes surrounding plaques in AD is in agreement with previous studies [ 28 , 29 ]. In contrast, our findings that MAO-B levels increase in pyramidal neurons in the frontal cortex, hippocampus CA1 and entorhinal cortex in AD have to our knowledge not been reported previously.…”

“…MAO-B is considered to be localized in the outer mitochondrial membrane. However, this is not the sole subcellular location because it has also been found in other compartments, including ER and lysosomes [ 29 ]. γ-Secretase is believed to be localized predominantly to Golgi, ER, the plasma membrane, endosomes and lysosomes [ 30 ].…”

“…If mitochondrial MAO-B interacts with γ-secretase, it is likely that the interaction takes place in the ER–mitochondrial interface (MAM), because γ-secretase has been suggested to be enriched in the ER part of the MAM [ 31 , 32 ]. Notably, it has been reported that MAO-A, an isoenzyme with different but overlapping substrate binding properties compared to MAO-B, interacts with PS1, and it was suggested that the interaction is mediated via the cytoplasmic loop/substrate binding site of PS1 [ 29 ]. MAO-B and MAO-A share approximately 70% sequence identity and have very similar chain folds [ 33 ], suggesting that MAO-A and MAO-B may have similar γ-secretase binding sites.…”

“…Further support for the connection between MAO-B and AD comes from clinical studies with MAO-B inhibitors, which have reported improved cognition and delayed AD progression [ 39 , 40 ]. It appears that the effects of MAO-B inhibitors in clinical trials are not only due to the effect on catalytic activity, but could also be due to the lowered release of H 2 O 2 and other reactive oxygen species, or hitherto nondefined functions [ 29 ]. Moreover, both the data presented here and previous reports showing enhanced MAO-B levels in PiB + MCI cases, but not in PiB – MCI cases [ 16 ], suggest that there is a correlation between MAO-B and Aβ pathology in AD.…”

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).…”