Grant: Doctoral Award - Frederick Banting and Charles Best Canada Graduate Scholarships

In recent years, interest in monoamine oxidase inhibitors (MAOIs) has increased enormously due to reports of their neuroprotective properties, suggesting that they may also be useful for treating certain aspects of neurodegenerative disorders such as Alzheimer's disease (AD). The MAOI phenelzine and a breakdown product (metabolite) of phenelzine, beta-phenylethylidenehydrazine (PEH), have been shown to protect neurons and increase recovery in an animal model of stroke. In addition, phenelzine was also effective in alleviating neurological and behavioural symptoms in an animal model of multiple sclerosis, as well as reducing brain tissue damage in an animal model of traumatic brain injury. Both phenelzine and PEH increase brain levels of the inhibitory neurotransmitter GABA that may counteract a toxic increase in the excitatory neurotransmission (excitotoxicity) that is present in AD; scavenge and neutralize toxic aldehydes that are increased in AD; and inhibit an enzyme (primary amine oxidase) that produces toxic aldehydes and has been reported to have increased activity in AD. The drugs currently used for treating AD improve the patient quality of life for a short period of time but do little to slow the progression of the disease. Since phenelzine and PEH target several pathways implicated in AD, it appears from preliminary findings that both drugs could be useful in treating this disorder. Using a genetic mouse model of AD, we will investigate the ability of phenelzine and PEH to attenuate beta-amyloid plaque formation (an event central to development of AD that is exacerbated by toxic aldehydes), alterations in connections between neurons and increases in activation of glial cells. Furthermore, we will look at changes in levels of neurotransmitters, amino acids, toxic aldehyde-modified proteins and activities of several enzymes, including primary amine oxidase, in the animal model and in brain tissue from AD patients and elderly individuals without AD.