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

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Monoamine Oxidase-A Physically Interacts with Presenilin-1(M146V) in the Mouse Cortex Journal of Alzheimer’s Disease 28 (2012) 403–422 403 DOI 10.3233/JAD-2011-111241 IOS Press Monoamine Oxidase-A Physically Interacts with Presenilin-1(M146V) in the Mouse Cortex Zelan Weia, Geraldine G. Gabriela, Lewei Ruia, Xia Caoa, Paul R. Penningtona, Jennifer Chlan-Fourneyb, Adil J. Nazaralic, Glen B. Bakerd and Darrell D. Mousseaua,∗ aCell Signalling Laboratory, Department of Psychiatry, University of Saskatchewan, Saskatoon, Canada bDepartment of Anatomy and Cell Biology, University of Saskatchewan, Saskatoon, Canada cLaboratory of Molecular Cell Biology, College of Pharmacy and Nutrition, University of Saskatchewan, Saskatoon, Canada dNeurochemical Research Unit, Department of Psychiatry, University of Alberta, Edmonton, Canada Accepted 8 September 2011 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(Ex9) 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. Keywords: Alzheimer’s disease, depression, mitochondria, monoamine oxidase, secretase INTRODUCTION and noradrenaline which are central to the neurobiol- ogy of depression [1, 2]. While the role of the MAO-B The mitochondrial enzyme monoamine oxidase isoform in neurodegeneration has been widely stud- (MAO) degrades neurotransmitters such as serotonin ied [3], that of the MAO-A isoform (discussed below) is often considered ancillary to its well-established role in depression. However, aspects of depression and neurodegeneration could certainly rely on overlapping ∗Correspondence to: D.D. Mousseau, Cell Signalling Laboratory, B45 HSB, University of Saskatchewan, 107 Wiggins Rd., Saska- molecular mechanisms. toon, SK (S7N 5E5), Canada. Tel.: +1 (306) 966 8824; E-mail: Alzheimer’s disease (AD) is clinically character- [email protected]. ized by a progressive loss of memory and executive ISSN 1387-2877/12/$27.50 © 2012 – IOS Press and the authors. All rights reserved 404 Z. Wei et al. / Presenilin-1 Regulates MAO-A Function function, yet earlier stages of AD also present with with the mitochondria, aptly called the mitochondria- non-cognitive symptoms including depression [4]. associated membrane (MAM) [37]. Given that protein Depression might represent a prodrome for AD-related contacts at the MAM facilitate communication and dementia in certain patients [5–7], with the rate of metabolic exchange between these two organelles [38], dementia increasing by 13% in a given patient for it is reasonable to consider that PS-1 could functionally every hospital admission based on a depressive episode influence mitochondrial-expressed proteins, including [8]. Given the acknowledged link between MAO-A MAO. and depression as well as the evidence that poly- A link between PS-1 and depression is strongly morphisms in the MAO-A promoter, particularly a suggested by the finding that pre-demented carri- variable number tandem repeat, have been linked to ers of the PS-1(A431E) and PS-1(L235V) variants increased risk of developing depression [9] as well are more likely to suffer from depression than non- as AD [10–12], we hypothesized that MAO-A repre- carrier siblings (note, the fact that the carriers are sents a commonality to depression and the early stages pre-demented and unaware of their genotype excludes of AD. This is supported a priori by the accumula- any possibility that their depression is reactive or tion in AD brains of toxic MAO-mediated metabolites secondary to a diagnosis of dementia/AD) [39]. Fur- [13] and with the early and progressive degeneration thermore, in transgenic animal models of AD-related of serotonin neurons in the dorsal raphe´ nucleus and pathology, the antidepressants imipramine, citalopram, noradrenergic neurons in the locus coeruleus [14–18]. and rolipram (also a phosphodiesterase inhibitor) In late-onset AD, both MAO-A activity and mRNA affect ␥-secretase-mediated substrate processing as have been shown to be elevated, although not neces- well as improve non-cognitive behavior via PS-1/␥- sarily concurrently, in cortical subregions, the locus secretase-sensitive mechanisms [40, 41]. In addition, coeruleus, thalamic nuclei, and white matter [19–22]. the AβPPSwe/PS-1(M146V) mouse model of amyloi- MAO-A activity has also been found to be decreased dosis exhibits changes in monoaminergic tone [42] and in late-onset AD brains [19, 23], but the 31% decrease non-cognitive behaviors [43], and the AβPPSwe/PS- in MAO-A activity in locus coeruleus is concomi- 1(Ex9) mouse exhibits a substantial monoaminergic tant with a nearly 70–80% neuronal cell loss [19, 23, neurodegeneration, particularly in serotonergic and 24]. This suggests that the average MAO-A activity noradrenergic systems [30, 31]. The latter occurs per surviving neuron is significantly increased [19]. independently of accumulation of either A␤ or phos- In AD patients, monoaminergic tone is unequivocally phorylated tau protein [30]. Thus monoaminergic affected [25] and MAO-A activity or the number of insult appears to represent an early event in AD-related MAO-A immunoreactive neurons has also been impli- pathology. cated in cognitive decline [23]. A role for MAO-A in Given the interest in placing the mitochondrion as a neurodegeneration is further supported by the observa- pivotal component in the early stages of AD progres- tion that estrogen, a putative neuroprotective hormone, sion [44], the changes in monoaminergic function in can selectively decrease MAO-A activity and mRNA experimental and clinical AD, and the link between levels in vivo [26, 27], whereas caspase-3-dependent PS-1 variants and depression, it is important to define apoptotic neuronal phenotypes following serum with- the role for MAO in this context. We now provide drawal or treatment with staurosporine are prevented data that support PS-1(M146V) as a negative regula- by selective MAO-A inhibition [28, 29]. tor of MAO-A function in the sensorimotor cortex, a Recently, monoaminergic dysfunction in the con- region affected during the progression of clinical AD text of AD has been associated with the presenilin-1 [45]. Furthermore, subcellular fractionation, confocal (PS-1)/␥-secretase pathway [30, 31]. The PS-1 pro- microscopy, and co-immunoprecipitation experiments tein is the catalytic core of the ␥-secretase complex provide strong evidence that MAO-A interacts directly that processes the amyloid-␤ protein precursor to the with PS-1 proteins. Mutations in the PSEN-1 gene pri- amyloid-␤ (A␤) 40- and 42-mer peptides [32, 33]. marily account for the early-onset form of AD and PS-1 has been associated with the mitochondria [34, fewer than 10% of all cases of AD. However, there is 35], which supports an influence of PS-1 beyond evidence that a mutation in PSEN-1, e.g., the one cod- the endoplasmic reticulum, one of its primary sites ing for the R249H substitution [46], is associated with of action [36]. Furthermore, within the endoplasmic the more common late-onset form of AD. Thus our reticulum itself, presenilins are heterogeneously dis- demonstrated interaction between PS-1 and MAO-A tributed, with a significant protein density being found could provide an explanation for a subtle role for PS-1 in the membrane subcompartment at the interface in non-cognitive neuropsychiatric disorders such as Z. Wei et al. / Presenilin-1 Regulates MAO-A Function 405 depression. By extension, an influence of PS-1 on [47–49]. In all experiments, PS-1(M146V) mice MAO-A function could also account for the ambiguity were compared with their wildtype (WT) litter- surrounding the role of MAO-A in both early-onset and mates. Mice were treated in accordance with the late-onset AD-related pathology. Further characteriza- University Committee on Animal Care and Sup- tion of this interaction in PS-1- and MAO-A-dependent ply/Canadian Council on Animal Care guidelines. pathologies is clearly warranted. MATERIALS AND METHODS Immunodetection and immunoprecipitation Reagents and antibodies Standard Western/SDS-PAGE denaturing condit- ions were used to detect expression of targeted proteins ◦ 5-Hydroxytryptamine (5-HT), N-[N-(3, 5-difluoro- (precleared; 12,000 × g, 10 min, 4 C; 20–30 ␮g/lane) phenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester or in immunoprecipitates (200–500 ␮g) precipitated (DAPT) and the ␤-actin and FLAG antibodies with protein-A/G Sepharose [50]. For immuno- were purchased from Sigma-Aldrich (Oakville, ON, precipitation experiments, non-specific binding to Canada). [14C]-5-HT (NEC-225) was purchased from immunoglobulin (IgG) was avoided by preclearing PerkinElmer Life Sciences (Waltham, MA, USA).
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