- Research article
- Open Access
Calcium-sensitive regulation of monoamine oxidase-A contributes to the production of peroxyradicals in hippocampal cultures: implications for Alzheimer disease-related pathology
© Cao et al; licensee BioMed Central Ltd. 2007
- Received: 12 May 2007
- Accepted: 16 September 2007
- Published: 16 September 2007
Calcium (Ca2+) has recently been shown to selectively increase the activity of monoamine oxidase-A (MAO-A), a mitochondria-bound enzyme that generates peroxyradicals as a natural by-product of the deamination of neurotransmitters such as serotonin. It has also been suggested that increased intracellular free Ca2+ levels as well as MAO-A may be contributing to the oxidative stress associated with Alzheimer disease (AD).
Incubation with Ca2+ selectively increases MAO-A enzymatic activity in protein extracts from mouse hippocampal HT-22 cell cultures. Treatment of HT-22 cultures with the Ca2+ ionophore A23187 also increases MAO-A activity, whereas overexpression of calbindin-D28K (CB-28K), a Ca2+-binding protein in brain that is greatly reduced in AD, decreases MAO-A activity. The effects of A23187 and CB-28K are both independent of any change in MAO-A protein or gene expression. The toxicity (via production of peroxyradicals and/or chromatin condensation) associated with either A23187 or the AD-related β-amyloid peptide, which also increases free intracellular Ca2+, is attenuated by MAO-A inhibition in HT-22 cells as well as in primary hippocampal cultures.
These data suggest that increases in intracellular Ca2+ availability could contribute to a MAO-A-mediated mechanism with a role in AD-related oxidative stress.
- Alzheimer Disease
- MAOA Activity
- Increase MAOA Activity
- Untreated Depressed Patient
MAO-A and MAO-B, two isoforms of monoamine oxidase (MAO), are expressed on the mitochondrial outer membrane. MAO-mediated neurodegeneration can result from the formation of hydrogen peroxide (H2O2) as a by-product of metabolism of aminergic neurotransmitters including serotonin and dopamine. If it is not detoxified by antioxidant systems such as glutathione peroxidase – one of the most abundant such systems in brain  – then H2O2 can be converted by iron-mediated Fenton reactions to hydroxyl radicals that can initiate lipid peroxidation and cell death. This is exacerbated when antioxidant systems are compromised, such as during aging . The reduction in the efficacy of these systems may simply be aggravated in chronic disease states such as Alzheimer disease (AD).
It has been demonstrated that inhibitors of MAO-B, such as l-deprenyl and, more recently, rasagiline, are effective in the management of early symptoms of Parkinson's disease in the clinic and in animal models [4–6] as well as in patients with mild AD-type dementia [4, 7]. Both MAO-B-positive astrocytes  and reactive oxygen species (ROS)  have been found in the vicinity of β-amyloid (Aβ) plaques. L-Deprenyl and rasagiline, however, may exert some of their effects independently of MAO-B as the neuroprotection mediated by these drugs is often associated with concentrations of the drug that are well below those required for inhibition of the enzyme , and has been associated with activation of Bcl-2 family members, interactions with the mitochondrial pore complex, and modulation of amyloid precursor protein cleavage .
MAO-A also plays a role in neuropsychiatric and behavioral disorders. The importance of this isoform is suggested by the aggressive phenotype seen in male mice deficient in MAO-A  and in males in a Dutch kindred bearing a spontaneous mutation (resulting in a premature stop) in the mao-A gene . Similarly, maltreated children, whose genotype confers low levels of MAO-A expression, more often develop conduct disorder, antisocial personality and adult violent crime than do children with a high-activity MAO-A genotype . Relatively modest changes in MAO-A activity/function can have important neuropsychiatric consequences as demonstrated by the fact that [11C]-harmine-labeled MAO-A is elevated by only 34% throughout the brain of untreated depressed patients compared to controls, yet it appears to be the major contributor to monoamine metabolism in these same patients . Depression not only may promote cognitive impairment, but also may be a risk factor for AD . Not surprisingly, MAO-A, which is often targeted for the treatment of depression, is also a potential risk factor for late-onset AD [15–18]. In contrast to irreversible inhibitors of MAO-A such as clorgyline, reversible inhibitors such as moclobemide are better tolerated and have been particularly efficacious in treating depression [19, 20] and cognitive disorders  in the elderly. In addition, they protect against apoptosis  and glutamate-induced excitotoxicity in vitro. Inhibition of MAO-A activity protects against striatal damage produced by the mitochondrial poison malonate and appears to rely on attenuation of dopamine-derived ROS , while apoptosis following serum starvation is reduced in MAO-A deficient cortical brain cells .
The NMDA-subtype of glutamate receptor has been linked to massive increases in mitochondrial Ca2+ accumulation . It is interesting that activation of this same receptor has been linked to Ca2+-dependent processes and pathology in [hepatic] encephalopathic brains  that correlates with a selective increase in MAO-A activity . The selectivity of Ca2+ for MAO-A is demonstrated ex vivo using brains from monkey , mouse  and rat , and is supported by the ability of the Ca2+-channel antagonist nimodipine to block the selective increase in MAO-A activity observed in senescence-accelerated mouse brain . Additional cations able to influence MAO-A function include Zn2+, which inhibits MAO-A activity , and Al3+ (another ion often linked to AD-like pathology), which activates it .
These combined observations, in addition to the fact that cytoplasmic free Ca2+ is elevated in aged neurons and even more so during neurodegeneration, such as that encountered during in AD [15, 34–36], certainly argue for examination of the relation between Ca2+ and MAO.
Antibodies and reagents
5-Hydroxytryptamine (5-HT), β-phenylethylamine (PEA), the β-actin antibody and protease inhibitor cocktail were bought from Sigma-Aldrich Co. [14C]-5-HT (NEC-225) and [14C]-PEA (NEC-502) were purchased from PerkinElmer Life Sciences. The MAO-A and CB-28K antibodies were purchased from Santa Cruz Biotechnology. IgG-HRP conjugates were obtained from Cedarlane Laboratories. All other reagents were purchased commercially.
Immortalized hippocampal cell cultures
The immortalized mouse hippocampal HT-22 cell line  was kindly provided by Dr. P. Maher (The Scripps Research Institute, La Jolla, CA, USA). Cells were cultured (5% CO2 at 37°C) in DMEM/low glucose medium containing 10% fetal bovine serum, 100 IU/mL penicillin G sodium salt and 0.03% glutamine.
Monoamine oxidase (MAO) activity
MAOA and -B activities (nmol/hr/mg protein) in HT-22 cell cultures were estimated radiochemically . Briefly, samples were homogenized in 80 volumes of oxygenated potassium phosphate buffer (0.2 M, pH 7.8) and incubated (100 μg/100 μl) for 10 min at 37°C with either 250 μM [14C]-5-HT (for MAO-A activity) or 50 μM [14C]-β-PEA (for MAO-B activity). The incubation was terminated by acidification and the labeled metabolites were extracted into ethyl acetate/toluene (1:1 vol/vol, water-saturated), an aliquot of which was subjected to scintillation spectrometry to determine radioactive content. MAO-A substrate kinetics was determined using protein (100 μg per reaction) from HT-22 cells pre-incubated in the absence or presence of Ca2+ (1 mM; 20 min, room temperature) and subsequently incubated with increasing concentrations of [14C]-5-HT [15 μM-4 mM]. Incubation in oxygenated potassium phosphate buffer (0.2 M, pH 7.8) and extraction of labeled metabolites proceeded as described above. Data were analyzed for estimates of Km and Vmax using the Prism v3.01 software.
Transient overexpression of CB-28K
The pREP-CB-28K (calbindin-D28K) plasmid expression vector was kindly provided by Dr. A. Pollock (University of California, San Francisco, CA). HT-22 cells were seeded in log phase and transfected with plasmid DNA (1–2 μg/well on a 24-well plate; seeded at 5 × 105 cells/well) using ExGen™500 (Fermentas) according to the manufacturer's directions. Expression of eGFP fluorescent protein revealed a transfection efficiency of approximately 50% using this technique. Cells were routinely harvested 24 h post-transfection.
Immunodetection of target proteins
Treated HT-22 cells were washed twice with ice-cold PBS and proteins were extracted in ice-cold lysis buffer (1% Triton X-100, 10% glycerol, 1 mM EDTA, 20 mM Tris, pH 7.5), containing protease inhibitor cocktail and 1 mM orthovanadate. Standard denaturing (SDS-PAGE) conditions were used to resolve proteins, which were then transferred to nitrocellulose. Protein expression in total cell lysates (20–30 μg/lane, precleared; 5000 × g, 10 min, 4°C) was visualized by enhanced chemiluminescence. Depicted immunoblots are representative of two-three independent experiments.
Determination of target mRNA by semi-quantitative reverse transcriptase-PCR (RT-PCR)
Total RNA from treated HT-22 cells was prepared with TRIZOL reagent according to the manufacturer's protocol and digested with RNase-free DNase to clear residual genomic DNA. First strand cDNA was reverse-transcribed from 2 μg of total RNA using oligo-(dT) (SuperScript™III First-Strand Synthesis System, Invitrogen). The cDNA was amplified using Taq polymerase and primer pairs (mao-A: forward: 5'-GAA GCT GAG CTC TCC TGT TAC-3'; reverse: 5'-ACA AAG CAG AGA AGA GCC AC-3'; mao-B: forward: 5'-GCT GAA GAG TGG GAC TAC ATG AC-3'; reverse: 5'-GGA ATG AAC CTT GGG AGG TG-3'; β-actin: forward: 5'-TAG AAG CAT TTG CGG TGC ACG-3'; reverse: 5'-TGC CCA TCT ATG AGG GTT ACG-3'). The resultant semi-quantitative PCR products were electrophoresed on agarose gel and visualized using ethidium bromide staining.
Fluorescence determination of free intracellular Ca2+
HT-22 cells were loaded with the fluorescent dye Fluo3-acetoxymethyl ester (Fluo-3-AM; Molecular Probes) at 4 μM for 30 min at 37°C . Fluorescence was visualized at an excitation wavelength of 488 nm and an emission wavelength of 550 nm on an Olympus FV300 Confocal Laser Scanning Biological Microscope.
Visualization of cytoplasmic peroxide radicals
2',7'-Dihydrodichlorofluorescein diacetate (DCFH2-DA)  permeates the cell membrane and is hydrolyzed to DCFH2, a nonfluorescent compound that remains trapped within the cell, but which yields a fluorescent product upon oxidation by H2O2. The cells were seeded on cover-slips. After treatment, the cells were rinsed twice with PBS and incubated with DCFH2-DA (5 μM, 30 min at 37°C) or DMSO, vehicle). The cells were washed in prewarmed HEPES-buffered (20 mM) HBSS (pH 7.0) containing 5 mM glucose, and prepared for DCF fluorescence (excitation: 488 nm; emission: 530 ± 15 nm).
Rat primary hippocampal culture
Animal care followed protocols and guidelines approved by University of Saskatchewan Animal Care Committee and the Canadian Council on Animal Care. Rat hippocampal cultures were prepared from E18 fetuses (time-pregnant Sprague-Dawley rats; Charles River Canada, Montreal, PQ, Canada) as described before with some modifications . In brief, the hippocampus was dissected in Ca2+- and Mg2+-free Hank's balanced salt solution (HBSS) supplemented with 15 mM HEPES and penicillin (100 U/ml)-streptomycin (100 μg/ml) (Gibco). Collected tissues were digested at 37°C with 0.25% trypsin-EDTA 15 min. The reaction was quenched with fetal bovine serum (FBS, 10%) and tissues were rinsed 3–4 times with HBSS to remove FBS. Following centrifugation at 800 × g for 10 min, the medium was removed and cells were resuspended in a chemically defined serum-free NeuroBasal medium supplemented with 1% N2, 2% B27, 50 μM L-glutamine, 15 mM HEPES, 10 U/ml penicillin and 10 μg/ml streptomycin. Neurons were then plated on coverslips (coated with 25 μg/ml poly-D-lysine), and grown at 37°C with 5% CO2-humidified atmosphere. The medium was replaced 24 h later with fresh NeuroBasal medium lacking L-glutamine and antibiotics. Medium was replaced after 4–5 days in vitro (DIV). Neurons were treated on DIV 7, following which they were fixed with 4% paraformaldehyde in 0.01 M PBS for 20 min at room temperature, washed several times with PBS, and stained with Hoechst 33258 (500 ng/ml, 10 min) for microscopic visualization of chromatin condensation (a characteristic of apoptotic cell death).
Significance (set at P < 0.05) was assessed by unpaired t-tests or by one-way ANOVA with post hoc analyses relying on Bonferonni's Multiple Comparison Test (GraphPad Prism v3.01). Data are represented as mean ± standard deviation (SD).
Low millimolar concentrations of Ca2+increase MAOA activity in HT-22 cells
The Ca2+ionophore A23187 increases MAO-A activity
Reduction of free intracellular Ca2+by overexpression of CB-28K reduces MAO-A activity
Immortalized and primary hippocampal toxicity associated with the Alzheimer disease-related peptide, Aβ, relies partly on a MAO-A sensitive mechanism
H2O2 is a natural by-product of MAO-A-mediated degradation of amines . The normal aging process and various neurodegenerative processes such as Parkinson's disease  and Alzheimer's disease [40, 41] could well be affected by oxidative stress associated with enhanced MAO-generated levels of H2O2.
We demonstrate that the selective response of MAO-A to Ca2+ (and its sensitivity to Mg2+, a physiologic Ca2+ antagonist ) occurs in immortalized HT-22 hippocampal cells and confirms observations using brain extracts from monkey , mouse , rat  and human (DDM: unpublished data). The effect of Ca2+ on MAO-A activity in our cultures appears modest; however, Meyer et al  have recently demonstrated that untreated depressed patients have levels of MAO-A density that are only 34% higher than that found in controls. Yet these same authors propose that this modest change could account for most of the change in biogenic amine levels observed in these patients. Obviously, small changes in MAO-A can significantly impact brain function.
While low millimolar levels of Ca2+ are necessary to reveal this effect, the fact that MAO-B activity remains unaffected clearly supports differences in MAO-A and MAO-B regulation. The need for millimolar concentrations also suggests pathological relevance. Interestingly, the mitochondria can modulate cytoplasmic Ca2+ homeostasis by accumulating Ca2+ into the very high micromolar range . Furthermore, elevated Ca2+ concentrations localized to microdomains may also represent unique means of modulating localized mitochondrial membrane and/or matrix function , including the activation of dehydrogenases . In neurons and chromaffin cells, mitochondria rapidly and reversibly buffer Ca2+ during cell stimulation to help clear large Ca2+ loads [46–48]. The ensuing overloading of mitochondria with Ca2+ may be involved in several pathological conditions, including ischemia-reperfusion lesions, neurotoxicity and neurodegenerative diseases, where ATP depletion, overproduction of ROS and release of apoptotic factors lead to cell damage .
Using the Ca2+ ionophore A23187, we now confirm that increasing free intracellular Ca2+ well above normal levels selectively increases MAO-A activity in living hippocampal HT-22 cells. The associated increase in peroxyradicals is moderately decreased by MAO-A inhibition, supporting a contribution by the enzyme to A23187-associated toxicity. Intracellular Ca2+ levels can also be quenched by specific proteins including calbindin-28K (CB-28K), the predominant Ca2+-binding protein in brain . Overexpression of CB-28K in HT-22 cells significantly decreased free Ca2+ levels and significantly decreased MAO-A activity. Again MAO-B activity was spared. The effects of both A23187 and CB-28K occurred independent of any change in the expression level of MAO-A protein (or mao-A gene), which, in combination with our demonstration of affinity changes of the MAO-A enzyme in the presence of Ca2+, suggests a functional modification of the MAO-A protein itself. These combined data implicate a CB-28K-dependent, Ca2+-sensitive component to MAO-A function, which could be exacerbated when CB-28K expression levels are compromised, such as in normal aging or, more importantly, during neurodegenerative processes [16, 34, 51]. In support of this, an age-related loss of CB-28K immunoreactive basal forebrain cholinergic neurons in cortical regions and in the dentate gyrus (hippocampus) has been shown in several species including dog, mouse and rat  and references therein). Furthermore, in AD-related pathology, a substantially greater loss of CB-28K immunoreactivity is observed, with the diminished capacity of the cell to buffer intracellular Ca2+ being considered as a core factor in the pathogenesis of AD [51–54]. This is corroborated by the ability of ectopic CB-28K to protect cell cultures against apoptosis, including that induced by the AD-related peptide β-amyloid [55–58] and by the fact that alterations in Ca2+ signalling can occur early in AD, well before any obvious extracellular Aβ deposition . Furthermore, dihydropyridine Ca2+ channel blockers, which are known to block the selective increase in MAO-A in the senescence-accelerated mouse model , may improve learning and performance in animals  and may improve age-associated and AD-related memory impairment in humans [61, 62]. As CB-28K and MAO-A immunoreactivities are often co-localized and cells immunoreactive for both proteins are reduced during AD [54, 63], it is not unreasonable to suppose that a loss of CB-28K could facilitate MAO-A-mediated H2O2 production in an increasingly toxic Aβ environment, leading to localized cell death. Treatment with Aβ(1–40) increases intracellular levels of Ca2+  [present study], possibly through its effect on the ryanodine receptor . A pathological contribution by MAO-A in AD is further suggested by the accumulation of toxic metabolites of MAO-mediated deamination in AD patients  as well as by the ability of MAO-A inhibition to reduce the ROS production associated with treatment of HT-22 cells with the AD-related Aβ(1–40) peptide (present study). Primary hippocampal neuronal cultures are also particularly sensitive to Aβ peptide  and Aβ-induced toxicity in these cells is also sensitive to MAO-A inhibition (present study). Experimentation based on in vivo assessment of the effect of Ca2+ on MAO-A as well as a closer examination of the relation between Ca2+/CB-28K and MAO-A in AD tissues is warranted.
MAO-A is a risk factor in AD and changes in MAO-A activity parallel changes in the production of ROS, e.g. H2O2. Given the neuroprotective role of CB-28K in human pathologies such as AD (and in models of AD), in addition to our demonstration that the toxicity of the AD-related peptide, Aβ, is sensitive to MAO-A inhibition, we suggest that part of the oxidative stress associated with AD may rely on a Ca2+/CB-28K-sensitive, MAO-A-mediated mechanism.
The availability of free intracellular Ca2+ is positively correlated with the activity of MAO-A, a mitochondrial H2O2-generating enzyme. The influence of Ca2+ on MAO-A function could potentially impact AD-related pathology, which is often associated with altered Ca2+ homeostasis, mitochondrial dysfunction and oxidative stress.
This work was funded, in part, by the Canadian Institutes of Health Research and by the Saskatchewan Health Research Foundation (DDM) and, in part, by the Aruna and Kripa Thakur award (XC), Department of Psychiatry, University of Saskatchewan. ZW is a recipient of a CIHR/Rx&D Research Program & AstraZeneca/Alzheimer Society of Canada Fellowship.
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