Alzheimer disease-related presenilin-1 variants exert distinct effects on monoamine oxidase-A activity in vitro

Abstract

Monoamine oxidase-A (MAO-A) has been associated with both depression and Alzheimer disease (AD). Recently, carriers of AD-related presenilin-1 (PS-1) alleles have been found to be at higher risk for developing clinical depression. We chose to examine whether PS-1 could influence MAO-A function in vitro. Overexpression of selected AD-related PS-1 variants (wildtype, Y115H, ΔEx9 and M146V) in mouse hippocampal HT-22 cells affects MAO-A catalytic activity in a variant-specific manner. The ability of the PS-1 substrate-competitor DAPT to induce MAO-A activity in cells expressing either PS-1 wildtype or PS-1(M146V) suggests the potential for a direct influence of PS-1 on MAO-A function. In support of this, we were able to co-immunoprecipitate MAO-A with FLAG-tagged PS-1 wildtype and M146V proteins. This potential for a direct protein-protein interaction between PS-1 and MAO-A is not specific for HT-22 cells as we were also able to co-immunoprecipitate MAO-A with FLAG-PS-1 variants in N2a mouse neuroblastoma cells and in HEK293 human embryonic kidney cells. Finally, we demonstrate that the two PS-1 variants reported to be associated with an increased incidence of clinical depression [e.g., A431E and L235V] both induce MAO-A activity in HT-22 cells. A direct influence of PS-1 variants on MAO-A function could provide an explanation for the changes in monoaminergic tone observed in several neurodegenerative processes including AD. The ability to induce MAO-A catalytic activity with a PS-1/γ-secretase inhibitor should also be considered when designing secretase inhibitor-based therapeutics.

Altered expression of γ-secretase components in animal model of major depressive disorder induced by reserpine administration

“…Furthermore, two PS-1 varients (A431E and L235V) increased the incidence of clinical depression by the induction of monoamine oxidase-A (MAO-A) activity [23]. But, our study was focused on the level of PS-2 expression in the brain of MDD animal model.…”

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

“…Carriers of AD-related presenilin-1 (PS-1) variants A431E and L235 V were found to have a higher rate of depression, as well as reduced 5-HT and NE levels (Liu et al 2008). 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).…”

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.…”