Monoamine Oxidase-A Physically Interacts with Presenilin-1(M146V) in the Mouse Cortex

Abstract

The concentration of presenilin-1 (PS-1) protein at the mitochondrial-associated aspect of the endoplasmic reticulum supports the potential for a mitochondrial influence of PS-1. Given that carriers of certain Alzheimer's disease (AD)-related PS-1 variants are predisposed to clinical depression and that depression has been historically associated with the mitochondrial enzyme, monoamine oxidase-A (MAO-A), we investigated cortical MAO-A function in the AD-related PS-1(M146V) knock-in mouse. The MAO-A system was clearly altered in the PS-1(M146V) mouse as revealed by (a) a mismatch between MAO-A protein expression and MAO-A activity; (b) changes in MAO-A-mediated monoaminergic neurotransmitter metabolism; (c) changes in non-cognitive behavior following treatment with the irreversible MAO-A inhibitor clorgyline; and (d) an increase in the potency of clorgyline in these same mice. We next investigated whether PS-1(M146V) could be influencing MAO-A directly. We observed (a) an enhanced MAO-A activity in necropsied PS-1(M146V) mouse cortical extracts incubated with DAPT (a PS-1 substrate-competitor); (b) the proximity of PS-1 with MAO-A and mitochondrial markers in cortical sections and in primary cortical neurons; (c) the co-segregation and co-immunoprecipitation of PS-1 and MAO-A within the mitochondrial fraction; and (d) the co-immunoprecipitation of overexpressed PS-1(M146V) and MAO-A proteins from N2a lysates. The PS-1(ΔEx9) and PS-1(D257A) variants, known to have low substrate-binding capacity, co-immunoprecipitated weakly with MAO-A. These combined data support a physical interaction between PS-1 and MAO-A that could influence MAO-A activity and contribute to the monoaminergic disruptions common to disorders as seemingly diverse as depression and AD.

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?

“…While this has never been pointedly examined, there is evidence, albeit indirect, in support of this possibility. For example, our recent work demonstrates that mice expressing the AD-related M146V-substituted presenilin-1 (PS-1) protein express significantly more cortical MAO-A protein than their wildtype littermates [124]; however, MAO-A activity in these mice remains comparable to wildtype levels, which suggests that the de novo pool of MAO-A protein is somehow rendered inactive. In these PS-1(M146V) mice there is a significant disruption of cortical cytoarchitecture and laminar organization [124] that is a phenotype reminiscent of the disrupted cortical lamination observed in both prenatal PS-1-null mice [125] and postnatal PS-1 conditional knockout mice [126].…”

“…Yet, similar permanent cytoarchitectural alterations are also evident in the somatosensory cortex of MAO-A-deficient mice [80], which, presumably, do not bear a PS-1 defect. One could argue that it is the hyperserotoninergic tone that is observed in both PS-1(M146V) [124] and MAO-A-deficient [80] mice that is the commonality underlying the cytoarchitectural alteration in these different strains of mice. This, again, is a reasonable assumption given the similar cortical disruptions associated with hyperserotoninergic (but not noradrenergic) tone produced by administration of the MAO-A inhibitor clorgyline to normal mice during their first week of life [127] or to the clorgyline-induced neurodevelopmental changes observed during in vitro embryogenesis [112].…”

Modulation of monoamine oxidase (MAO) expression in neuropsychiatric disorders: genetic and environmental factors involved in type A MAO expression

“…These two variant PS-1 forms increased MAO-A activity in mouse hippocampal HT-22 cells; PS-1 physically interacted with MAO-A to suppress its activity, whereas PS-1/c-secretase inhibitor DAPT (tbutyl 2-{2-[2-(3,5-difluorophenyl)acetamido]-propanamido}-2-phenylacetate), increased its activity significantly (Pennington et al 2011). In PS-1(M146V) knock-in mouse, the interaction of MAO-A with PS-1 was reduced, and MAO-A activity was up-regulated by direct activation (Wei et al 2012). Increased MAO-A activity might thus be associated with a higher risk for developing depression in carriers of AD-related PS-1 alleles (Ringman et al 2004).…”

Type A and B Monoamine Oxidase in Age-Related Neurodegenerative Disorders: Their Distinct Roles in Neuronal Death and Survival

“…By physical protein-protein interaction, wild and M146V variants of PS-1 exert distinct affects on MAO-A function in mouse hippocampal HT-22 cells and also in the brain cortex of M146V-knock-in mouse [94,95]. Two PS-1 variants associated with depression, A431E and L235V, increased MAO-A activity in HT-22 cells.…”