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

• Published in: Journal of Neural Transmission Vol. 118; no. 7; pp. 987 - 995
• Main Authors: Pennington, Paul R., Wei, Zelan, Rui, Lewei, Doig, Jennifer A., Graham, Brett, Kuski, Kelly, Gabriel, Geraldine G., Mousseau, Darrell D.
• Format: Journal Article
• Language: English
• Published: Vienna Springer Vienna 01.07.2011; Springer Nature B.V
• Subjects: Alzheimer Disease - enzymology; Alzheimer Disease - genetics; Alzheimer Disease - pathology; Animals; Basic Neurosciences; Cell Line, Transformed; Cell Line, Tumor; Depressive Disorder - enzymology; Depressive Disorder - genetics; Depressive Disorder - pathology; Genetic Variation; Genetics and Immunology - Original Article; HEK293 Cells; Humans; Medicine; Medicine & Public Health; Mice; Monoamine Oxidase - metabolism; Neuroblastoma - enzymology; Neuroblastoma - pathology; Neurology; Neurons - cytology; Neurons - enzymology; Neurosciences; Presenilin-1 - genetics; Presenilin-1 - physiology; Psychiatry; Presenilin; Oxidative stress; Neuron; Monoamine oxidase; Alzheimer disease; Secretase
• DOI: 10.1007/s00702-011-0616-7
• ISSN: 0300-9564

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.