Presenilin-1 (PS-1) is the catalytic core of the ã-secretase complex, which is best known for its role in the generation of the Alzheimer disease (AD)-related â-amyloid peptide. Mutated forms of PS-1 are known to be associated with particularly aggressive forms of AD. Changes in monoaminergic neurotransmitter systems, including the serotonin and norepinephrine systems, have long been associated with some of the earliest events in AD, whereas changes in the availability of these same monoamines have historically been associated with clinical depression. Therefore, it is not surprising that depression has now been proposed as a risk factor for developing AD and that pre-demented carriers of mutated forms of PS-1 are more prone to developing depression. MAO-A is historically associated with depression and is also a known risk factor for AD. Given this, I hypothesized that MAO-A represents a neurochemical link between depression and AD, and I chose to examine the influence of PS-1 mutations on MAO-A function in vivo/ex vivo and in vitro.<p> I first focused on the PS-1(M146V) knock-in mouse model of AD-related PS-1/ã-secretase function. I used a radioenzymatic assay to estimate MAO-A catalytic activity and western blot analysis to determine MAO-A protein expression, and found that MAO-A activity does not correlate with MAO-A expression in the cortex and cerebellum of the PS-1(M146V) mice. Furthermore, the potency of the MAO-A inhibitor clorgyline (CLG) is greater in both the cortex and cerebellum of the PS-1(M146V) mice compared to the potency of CLG in wildtype littermates. CLG dose-response curves suggest that there might be a change in cooperativity in the MAO-A protein from PS-1(M146V) cortex (which would suggest a change in conformation and/or access of the substrate to the catalytic pocket in MAO-A). High-pressure liquid chromatography was used to analyze monoamine levels in these same regions. The levels of monoamines (i.e. serotonin, dopamine and norepinephrine) suggest that PS-1 (M146V) inhibits MAO-A function in the cortex, but not in the cerebellum. Furthermore, CLG has no significant effect on amine levels in cortex, but tends to increase their accumulation in cerebellum.<p> The overexpression of PS-1 (M146V) in neuronal cultures reveals that this protein affects MAO-A activity and, more importantly, the PS-1(M146V) protein co-precipitates with MAO-A, thus suggesting a possibility for a direct protein-protein interaction. This is supported by the observation that MAO-A activity is increased in cell extracts incubated with the PS-1 substrate-competitor, N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester (DAPT). Preliminary studies have been undertaken to determine the motif in MAO-A that could be acting as a binding site/target site for PS-1.<p> These combined results support the hypothesis that PS-1 proteins can influence MAO-A function and, furthermore, that MAO-A is a novel interactor for PS-1/ã-secretase. This could well explain some of the ambiguous literature associated with both of these proteins in disorders as diverse as depression and AD.

The enzyme monoamine oxidase (MAO) is linked to mental disorders such as depression and neurodegenerative diseases. Our laboratory has recently demonstrated that increases in calcium (Ca2+) can enhance MAO activity and that this might contribute to Alzheimer disease (AD). AD has been linked to gain-of-function mutations in the presenilin-1 (PS-1) protein that not only promote the generation of the toxic amyloid-â peptide, but that also alter intracellular Ca2+ availability. <p>Radioenzymatic MAO assays were used to demonstrate that over-expression of different AD-related PS-1 mutant proteins, i.e. Y115H, ÄEx9 and M146V, in hippocampal-derived HT-22 cells alter either basal and/or Ca2+-sensitive MAO-A activity. The effects of PS-1 mutant proteins on the availability of intracellular Ca2+ are not consistent suggesting that this may not be the primary means of regulating MAO activity. The sensitivity of MAO to Ca2+ was also demonstrated in cortical (both MAO-A and MAO-B responded to Ca2+) and cerebellar (only MAO-A responded to Ca2+) samples from transgenic mice overexpressing the PS-1 (M146V) mutation. These changes in MAO coincided with changes in the availability of the neurotransmitters dopamine, noradrenaline and serotonin in the cerebellum, but not in the cortex, and reflect the known regional differences in neurotransmitter regulation. Immunoprecipitation studies and the observed increase in MAO-A activity following in vitro chemical inhibition of the ã-secretase complex (comprising several proteins including PS-1) support the notion that PS-1 constitutively associates with MAO-A. These effects on Ca2+-sensitive MAO function could contribute to AD-related pathology and could also contribute to the depression often associated with AD.

Monoamine oxidases (MAOs) are phylogenetically old enzymes which catalyze the deamination of monoamines. Interest in a relationship between MAO and aggressive behaviour derives from the report of a single family with a mutation which obliterates the activity of MAO A, as well as a long history of studies which substantiate a relationship between MAO activity and impulsive aggressive behaviour. The goals of this thesis were: (1) to examine the generalizability of the specific MAO mutation noted above; (2) to evaluate the relationship between platelet MAO activity and genetic polymorphisms in MAO genes, and (3) to extend knowledge regarding the developmental behavioural impact of MAO deficiency in mice treated pre- and perinatally with inhibitors of MAO. / In the first study we genotyped the C936T mutation in 100 subjects followed longitudinally and oversampled for aggressive behaviour. None of the subjects in our sample carried this mutation. / In the second study, we report the lack of association between platelet MAO activity and four intronic microsatellite polymorphisms of the MAO genes. / Studies of MAO knockout mice are at significant variance with clinical pharmacological experience using MAO inhibitors. Prompted by this and by other seminal basic experiments, we hypothesized that inhibition of MAO activity during the developmental period would have profound behavioural effects. MAO A and B inhibitors were administered, separately or in combination, to mice during gestation and lactation. Total prenatal MAO inhibition produced a severe pattern of behaviour, while MAO-B inhibited mice demonstrated a similar pattern with lower intensity. Aggression was elevated in MAO-A inhibited mice only after acute pharmacological challenges suggesting prenatal sensitization. Thus developmental inhibition of MAO activity engenders behavioural effects which parallel those observed in animals devoid functional MAO. These data underscore the importance of neurochemical changes during development and provide a possible model for uninhibited aggression, common in clinical populations.

Thesis (M.Sc.)--University of Adelaide, Dept. of Physiology, 1977.

No description available.

The mitochondrial membrane bound flavoenzymes monoamine oxidase A and B (MAO-A and MAO-B) catalyze the a-carbon oxidation of a variety of amines including neurotransmitters such as dopamine and serotonin. Although the primary structures of these enzymes have been established from the corresponding gene sequences, relatively little is known regarding the structural features of the active sites which lead to the selectivities observed with various substrates and inhibitors. In spite of many efforts, these enzymes have not been crystallized. In the absence of X-ray structures, the design, synthesis, and evaluation of biological activity remain the only way to assess a view of the active sites, through SAR and QSAR studies. The excellent MAO-A and/or B substrate and inhibitor properties of various 1,4-disubstituted-1,2,3,6-tetrahydropyridine derivatives offer an interesting opportunity to probe the active sites of MAO-A and MAO-B. In an effort to explore the spatial features of the active sites, we have synthesized series of substituted tetrahydropyridines, evaluated their biological activity with purified MAO-A and MAO-B, and carried out a topological analysis of the MAO active sites using molecular modeling. In addition, the results described in this thesis provide evidence that the MAO-A and MAO-B active sites differ in shape, regions of activity, and areas that tolerate polar interactions. The role of MAO in neurodegenerative processes such as Parkinson's Disease has been recognized for some time. The structurally unique parkinsonian inducing substrate 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is bioactivated to neurotoxic metabolites. The mechanism of neurotoxicity has been studied extensively and it is known that MAO-B catalyzes the conversion of MPTP to the 2,3-dihydro-1-methyl-4-phenylpyridinium species (MPDP+) which undergoes further oxidation to the neurotoxic metabolite 1-methyl-4-phenyl pyridnium (MPP+). However, the role of MAO-A in mediating a neurotoxic response, has not been fully defined due to the lack of selective MAO-A substrates. In this thesis, we have investigated the neurotoxic potential of several tetrahydropyridines in C57Bl/6 mice and the ability of selective inhibitors to protect against the expression of MAO mediated neurotoxicity. / Ph. D.

No description available.

by Kwok-Ping Ho. / Thesis (M.Phil.)--Chinese University of Hong Kong, 1980. / Bibliography: leaves 111-118.

Cathinones are psychostimulant compounds heavily implicated as drugs of abuse. They exert their physiological actions at the monoamine transporters, which are responsible for maintaining synaptic neurotransmitter homeostasis. Monoamine transporters produce currents during transport and have been shown to depolarize cell membranes and activate voltage-gated calcium channels in mammalian expression systems. This phenomenon is harnessed in an assay which measures these induced calcium transients, allowing for quantification of pharmacodynamic effects of compounds at monoamine transporters. It is unknown if this electrical coupling occurs in neurons, but the implications if it does are significant. In the current work, fluorescent resonance energy transfer studies of HEK cells expressing hDAT suggest that a subpopulation of monoamine transporters and calcium channels may be interacting directly. Additionally, this work presents calcium assay data comparing several novel methcathinone analogs. Of the compounds tested, a single α-methyl substituent at the α-carbon yields the greatest potency at hDAT. The implications of these results shed light on future psychostimulant studies and further define the physiological relationship of the components of a system used to study these compounds.

Background: Several neuropsychiatrie disorders have shown season of birth associations. Low cerebrospinal fluid (CSF) levels of the serotonin metabolite 5-HIAA and the dopamine metabolite HVA have been associated with suicidal behaviour, impulsivity, and aggression. This thesis investigated associations between the season of birth, the CSF levels of three monoamine metabolites (including MHPG of norepinephrine), the scales of the diagnostic interview for borderline patients (DIB), and psychiatric diagnoses. Also, the methods of suicide were investigated in relation to the season of birth. Methods: We studied a clinical sample of 241 patients in Stockholm with mood, anxiety and adjustment disorders with respect to the CSF levels of monoamine metabolites in relation to the season of birth, and in relation to the DIB in an overlapping sample. We also analysed all completed suicides during the 42 years 1952- 1993inVästerbottenin northern Sweden (1466 cases) by multiple logistic regressions to relate suicide methods with season of birth, gender, age, urban-rural residence, marital status, year of suicide, and season of suicide. For the 20 years 1961- 1980 (693cases), psychiatric in-patient and out-patient records were also examined for any history of psychiatric contacts and psychiatric diagnoses. In two mutually independent samples, we investigated the DIB in relation to the season of birth. Results: In the Stockholm sample, those born during February to April had significantly lower CSF levels of 5-HIAA, and those born during October to January had significantly higher CSF levels of HVA, HVA/5-HIAA, and HVA/MHPG, as well as (non-significantly) higher levels of 5-HIAA. Those with an intermediate score of section II (impulse action patterns) of the DIB had significantly higher CSF levels of 5-HIAA and HVA, and they were significantly more likely to have been born during October to January. In the Västerbotten register, those born during February to April were significantly more likely to have preferred hanging rather than poisoning or petrol gases, and conversely for those born during October to January. These associations with suicide methods were found for the total sample and for those without any history of psychiatric contacts, but not for those with psychiatric contacts. Conclusions: Suicidal behaviour shows statistically significant variation according to the season of birth, most probably mediated by a variation in an independent trait of vulnerability to suicide based on neurodevelopmental parameters, particularly the serotonergic system. The suicidal process differs between those who seek psychiatric care compared to those who do not, reflecting differences in the diagnostic spectra and in the extent of mental illness. / <p>Härtill 6 delarbeten.</p>