caa a22 4500 445376449 CHVBK 20180317143004.0 cr unu---uuuuu 170323e20110701xx s 000 0 eng 10.1007/s00702-011-0616-7 doi (NATIONALLICENCE)springer-10.1007/s00702-011-0616-7 Alzheimer disease-related presenilin-1 variants exert distinct effects on monoamine oxidase-A activity in vitro [Elektronische Daten] [Paul Pennington, Zelan Wei, Lewei Rui, Jennifer Doig, Brett Graham, Kelly Kuski, Geraldine Gabriel, Darrell Mousseau] 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. Springer-Verlag, 2011 Secretase nationallicence Neuron nationallicence Oxidative stress nationallicence Monoamine oxidase nationallicence Alzheimer disease nationallicence Presenilin nationallicence Pennington Paul Cell Signalling Laboratory, Department of Psychiatry, University of Saskatchewan, B45 HSB, 107 Wiggins Rd, S7N 5E5, Saskatoon, SK, Canada aut Wei Zelan Cell Signalling Laboratory, Department of Psychiatry, University of Saskatchewan, B45 HSB, 107 Wiggins Rd, S7N 5E5, Saskatoon, SK, Canada aut Rui Lewei Cell Signalling Laboratory, Department of Psychiatry, University of Saskatchewan, B45 HSB, 107 Wiggins Rd, S7N 5E5, Saskatoon, SK, Canada aut Doig Jennifer Cell Signalling Laboratory, Department of Psychiatry, University of Saskatchewan, B45 HSB, 107 Wiggins Rd, S7N 5E5, Saskatoon, SK, Canada aut Graham Brett Cell Signalling Laboratory, Department of Psychiatry, University of Saskatchewan, B45 HSB, 107 Wiggins Rd, S7N 5E5, Saskatoon, SK, Canada aut Kuski Kelly Cell Signalling Laboratory, Department of Psychiatry, University of Saskatchewan, B45 HSB, 107 Wiggins Rd, S7N 5E5, Saskatoon, SK, Canada aut Gabriel Geraldine Cell Signalling Laboratory, Department of Psychiatry, University of Saskatchewan, B45 HSB, 107 Wiggins Rd, S7N 5E5, Saskatoon, SK, Canada aut Mousseau Darrell Cell Signalling Laboratory, Department of Psychiatry, University of Saskatchewan, B45 HSB, 107 Wiggins Rd, S7N 5E5, Saskatoon, SK, Canada aut Journal of Neural Transmission Springer Vienna 118/7(2011-07-01), 987-995 0300-9564 118:7<987 2011 118 702 https://doi.org/10.1007/s00702-011-0616-7 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/s00702-011-0616-7 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Pennington Paul Cell Signalling Laboratory, Department of Psychiatry, University of Saskatchewan, B45 HSB, 107 Wiggins Rd, S7N 5E5, Saskatoon, SK, Canada aut NATIONALLICENCE 700 1- Wei Zelan Cell Signalling Laboratory, Department of Psychiatry, University of Saskatchewan, B45 HSB, 107 Wiggins Rd, S7N 5E5, Saskatoon, SK, Canada aut NATIONALLICENCE 700 1- Rui Lewei Cell Signalling Laboratory, Department of Psychiatry, University of Saskatchewan, B45 HSB, 107 Wiggins Rd, S7N 5E5, Saskatoon, SK, Canada aut NATIONALLICENCE 700 1- Doig Jennifer Cell Signalling Laboratory, Department of Psychiatry, University of Saskatchewan, B45 HSB, 107 Wiggins Rd, S7N 5E5, Saskatoon, SK, Canada aut NATIONALLICENCE 700 1- Graham Brett Cell Signalling Laboratory, Department of Psychiatry, University of Saskatchewan, B45 HSB, 107 Wiggins Rd, S7N 5E5, Saskatoon, SK, Canada aut NATIONALLICENCE 700 1- Kuski Kelly Cell Signalling Laboratory, Department of Psychiatry, University of Saskatchewan, B45 HSB, 107 Wiggins Rd, S7N 5E5, Saskatoon, SK, Canada aut NATIONALLICENCE 700 1- Gabriel Geraldine Cell Signalling Laboratory, Department of Psychiatry, University of Saskatchewan, B45 HSB, 107 Wiggins Rd, S7N 5E5, Saskatoon, SK, Canada aut NATIONALLICENCE 700 1- Mousseau Darrell Cell Signalling Laboratory, Department of Psychiatry, University of Saskatchewan, B45 HSB, 107 Wiggins Rd, S7N 5E5, Saskatoon, SK, Canada aut NATIONALLICENCE 773 0- Journal of Neural Transmission Springer Vienna 118/7(2011-07-01), 987-995 0300-9564 118:7<987 2011 118 702 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer