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.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Agbayewa MO (1986) Earlier psychiatric morbidity in patients with Alzheimer’s disease. J Am Geriatr Soc 34:561–564
Ankarcrona M, Hultenby K (2002) Presenilin-1 is located in rat mitochondria. Biochem Biophys Res Commun 295:766–770
Arai H et al (1984) Changes of biogenic amines and their metabolites in postmortem brains from patients with Alzheimer-type dementia. J Neurochem 43:388–393
Berger AK et al (1999) The occurrence of depressive symptoms in the preclinical phase of AD: a population-based study. Neurology 53:1998–2002
Burke WJ et al (2004) Neurotoxicity of MAO metabolites of catecholamine neurotransmitters: role in neurodegenerative diseases. Neurotoxicology 25:101–115
Cao X et al (2007) Calcium-sensitive regulation of monoamine oxidase-A contributes to the production of peroxyradicals in hippocampal cultures: implications for Alzheimer disease-related pathology. BMC Neurosci 8:73
Cao X et al (2009a) Calcium alters monoamine oxidase-A parameters in human cerebellar and rat glial C6 cell extracts: possible influence by distinct signalling pathways. Life Sci 85:262–268
Cao X et al (2009b) Serine 209 resides within a putative p38(MAPK) consensus motif and regulates monoamine oxidase-A activity. J Neurochem 111:101–110
Capell A et al (2000) Presenilin-1 differentially facilitates endoproteolysis of the beta-amyloid precursor protein and Notch. Nat Cell Biol 2:205–211
Caraci F et al (2010) Depression and Alzheimer’s disease: neurobiological links and common pharmacological targets. Eur J Pharmacol 626:64–71
Chan-Palay V (1992) Depression and senile dementia of the Alzheimer type: a role for moclobemide. Psychopharmacology (Berl) 106(Suppl):S137–S139
Chan-Palay V et al (1993) Calbindin D-28k and monoamine oxidase A immunoreactive neurons in the nucleus basalis of Meynert in senile dementia of the Alzheimer type and Parkinson’s disease. Dementia 4:1–15
Curcio CA, Kemper T (1984) Nucleus raphe dorsalis in dementia of the Alzheimer type: neurofibrillary changes and neuronal packing density. J Neuropathol Exp Neurol 43:359–368
Doan A et al (1996) Protein topology of presenilin 1. Neuron 17:1023–1030
Geerlings MI et al (2008) History of depression, depressive symptoms, and medial temporal lobe atrophy and the risk of Alzheimer disease. Neurology 70:1258–1264
Grudzien A et al (2007) Locus coeruleus neurofibrillary degeneration in aging, mild cognitive impairment and early Alzheimer’s disease. Neurobiol Aging 28:327–335
Grunblatt E et al (2005) Oxidative stress related markers in the “VITA” and the centenarian projects. Neurobiol Aging 26:429–438
Guo Q et al (1999) Increased vulnerability of hippocampal neurons to excitotoxic necrosis in presenilin-1 mutant knock-in mice. Nat Med 5:101–106
Hansson CA et al (2004) Nicastrin, presenilin, APH-1, and PEN-2 form active gamma-secretase complexes in mitochondria. J Biol Chem 279:51654–51660
Hebert SS et al (2003a) Oligomerization of human presenilin-1 fragments. FEBS Lett 550:30–34
Hebert SS et al (2003b) Dimerization of presenilin-1 in vivo: suggestion of novel regulatory mechanisms leading to higher order complexes. Biochem Biophys Res Commun 301:119–126
Ishii T (1966) Distribution of Alzheimer’s neurofibrillary changes in the brain stem and hypothalamus of senile dementia. Acta Neuropathol 6:181–187
Kang DE et al (2005) Presenilins mediate phosphatidylinositol 3-kinase/AKT and ERK activation via select signaling receptors. Selectivity of PS2 in platelet-derived growth factor signaling. J Biol Chem 280:31537–31547
Kennedy BP et al (2003) Early and persistent alterations in prefrontal cortex MAO A and B in Alzheimer’s disease. J Neural Transm 110:789–801
Kessing LV, Andersen PK (2004) Does the risk of developing dementia increase with the number of episodes in patients with depressive disorder and in patients with bipolar disorder? J Neurol Neurosurg Psychiatry 75:1662–1666
Kessing LV et al (2009) Antidepressants and dementia. J Affect Disord 117:24–29
Kosenko EA et al (2003) Calcium and ammonia stimulate monoamine oxidase A activity in brain mitochondria. Biol Bull Russ Acad Sci 30:449–452
Lin MT, Beal MF (2006) Alzheimer’s APP mangles mitochondria. Nat Med 12:1241–1243
Liu Y et al (2008) Amyloid pathology is associated with progressive monoaminergic neurodegeneration in a transgenic mouse model of Alzheimer’s disease. J Neurosci 28:13805–13814
Manczak M et al (2006) Mitochondria are a direct site of A beta accumulation in Alzheimer’s disease neurons: implications for free radical generation and oxidative damage in disease progression. Hum Mol Genet 15:1437–1449
Marcyniuk B et al (1986) Loss of nerve cells from locus coeruleus in Alzheimer’s disease is topographically arranged. Neurosci Lett 64:247–252
Mejia S et al (2003) Nongenetic factors as modifiers of the age of onset of familial Alzheimer’s disease. Int Psychogeriatr 15:337–349
Meyer JH et al (2006) Elevated monoamine oxidase a levels in the brain: an explanation for the monoamine imbalance of major depression. Arch Gen Psychiatry 63:1209–1216
Morohashi Y et al (2006) C-terminal fragment of presenilin is the molecular target of a dipeptidic gamma-secretase-specific inhibitor DAPT (N-[N-(3, 5-difluorophenacetyl)-l-alanyl]-S-phenylglycine t-butyl ester). J Biol Chem 281:14670–14676
Nishimura AL et al (2005) Monoamine oxidase a polymorphism in Brazilian patients: risk factor for late-onset Alzheimer’s disease? J Mol Neurosci 27:213–217
Parvizi J et al (2001) The selective vulnerability of brainstem nuclei to Alzheimer’s disease. Ann Neurol 49:53–66
Pugh PL et al (2007) Non-cognitive behaviours in an APP/PS1 transgenic model of Alzheimer’s disease. Behav Brain Res 178:18–28
Reddy PH et al (2010) Amyloid-beta and mitochondria in aging and Alzheimer’s disease: implications for synaptic damage and cognitive decline. J Alzheimers Dis 20(Suppl 2):S499–S512
Ringman JM et al (2004) Female preclinical presenilin-1 mutation carriers unaware of their genetic status have higher levels of depression than their non-mutation carrying kin. J Neurol Neurosurg Psychiatry 75:500–502
Roychaudhuri R et al (2009) Amyloid beta-protein assembly and Alzheimer disease. J Biol Chem 284:4749–4753
Rub U et al (2000) The evolution of Alzheimer’s disease-related cytoskeletal pathology in the human raphe nuclei. Neuropathol Appl Neurobiol 26:553–567
Sastre M et al (2001) Presenilin-dependent gamma-secretase processing of beta-amyloid precursor protein at a site corresponding to the S3 cleavage of Notch. EMBO Rep 2:835–841
Saura J et al (1994) Increased monoamine oxidase B activity in plaque-associated astrocytes of Alzheimer brains revealed by quantitative enzyme radioautography. Neuroscience 62:15–30
Schneider I et al (2001) Mutant presenilins disturb neuronal calcium homeostasis in the brain of transgenic mice, decreasing the threshold for excitotoxicity and facilitating long-term potentiation. J Biol Chem 276:11539–11544
Shalat SL et al (1987) Risk factors for Alzheimer’s disease: a case-control study. Neurology 37:1630–1633
Shen J, Kelleher RJ 3rd (2007) The presenilin hypothesis of Alzheimer’s disease: evidence for a loss-of-function pathogenic mechanism. Proc Natl Acad Sci USA 104:403–409
Sherif F et al (1992) Brain gamma-aminobutyrate aminotransferase (GABA-T) and monoamine oxidase (MAO) in patients with Alzheimer’s disease. J Neural Transm Park Dis Dement Sect 4:227–240
Smith IF et al (2002) Ca(2+) stores and capacitative Ca(2+) entry in human neuroblastoma (SH-SY5Y) cells expressing a familial Alzheimer’s disease presenilin-1 mutation. Brain Res 949:105–111
Szapacs ME et al (2004) Late onset loss of hippocampal 5-HT and NE is accompanied by increases in BDNF protein expression in mice co-expressing mutant APP and PS1. Neurobiol Dis 16:572–580
Takehashi M et al (2002) Association of monoamine oxidase A gene polymorphism with Alzheimer’s disease and Lewy body variant. Neurosci Lett 327:79–82
Thinakaran G, Sisodia SS (2006) Presenilins and Alzheimer disease: the calcium conspiracy. Nat Neurosci 9:1354–1355
Thinakaran G et al (1996) Endoproteolysis of presenilin 1 and accumulation of processed derivatives in vivo. Neuron 17:181–190
Thinakaran G et al (1997) Evidence that levels of presenilins (PS1 and PS2) are coordinately regulated by competition for limiting cellular factors. J Biol Chem 272:28415–28422
Thorpe L, Groulx B (2001) Depressive syndromes in dementia. Can J Neurol Sci 28(Suppl 1):S83–S95
Wei Z et al (2009) Haloperidol disrupts Akt signalling to reveal a phosphorylation-dependent regulation of pro-apoptotic Bcl-XS function. Cell Signal 21:161–168
Wiedemann N et al (2009) Connecting organelles. Science 325:403–404
Wu YH et al (2007) A promoter polymorphism in the monoamine oxidase A gene is associated with the pineal MAOA activity in Alzheimer’s disease patients. Brain Res 1167:13–19
Wuwongse S et al (2010) The putative neurodegenerative links between depression and Alzheimer’s disease. Prog Neurobiol 91:362–375
Yankner BA, Lu T (2009) Amyloid beta-protein toxicity and the pathogenesis of Alzheimer disease. J Biol Chem 284:4755–4759
Zweig RM et al (1988) The neuropathology of aminergic nuclei in Alzheimer’s disease. Ann Neurol 24:233–242
Acknowledgments
This study was funded by several graduate research awards, including College of Graduate Studies and Research Dean’s Scholarships (to GGG and LR) and a Canadian Institutes of Health Research Master’s Scholarship (to GGG), and successive College of Medicine Dean’s Research Project Awards (to BG). DDM currently holds the Saskatchewan Research Chair in Alzheimer’s Disease and Related Dementias funded jointly by the Alzheimer Society of Saskatchewan and Saskatchewan Health Research Foundation. There are no competing interests.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Pennington, P.R., Wei, Z., Rui, L. et al. Alzheimer disease-related presenilin-1 variants exert distinct effects on monoamine oxidase-A activity in vitro. J Neural Transm 118, 987–995 (2011). https://doi.org/10.1007/s00702-011-0616-7
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00702-011-0616-7