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      • HARVEST
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      • HARVEST
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      Characterization of a novel interaction between presenilin-1 and monoamine oxidase-A

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      Date
      2008-04-28
      Author
      Gabriel, Geraldine
      Type
      Thesis
      Degree Level
      Masters
      Metadata
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      Abstract
      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. 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.
      Degree
      Master of Science (M.Sc.)
      Department
      Psychiatry
      Program
      Psychiatry
      Supervisor
      Mousseau, Darrell D.
      Committee
      Richardson, J. Steven; Nazarali, Adil J.; Li, Xin-Min; Wu, Lingyun
      Copyright Date
      April 2008
      URI
      http://hdl.handle.net/10388/etd-04232008-201306
      Subject
      Calcium
      Alzheimer disease
      Presenilin-1
      Monoamine oxidase
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      • Graduate Theses and Dissertations
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