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2007 Grant - Colton
The Role of Nitric Oxide in the Pathology of Alzheimer's Disease
Carol A. Colton, Ph.D.
Duke University Medical Center
Durham, North Carolina
2007 Investigator-Initiated Research Grant
Alzheimer's disease is characterized by two key pathological features: (1) the assembly of beta-amyloid protein fragments into toxic structures and (2) the chemical alteration of tau proteins, which form abnormal structures called neurofibrillary tangles. The link between these two key features is not well understood.
Studies with genetically altered mice have been an important resource for characterizing the biology of Alzheimer's disease. A significant challenge, however, is developing a mouse model that not only creates both beta-amyloid and tau pathologies but also reveals the relationship between these features and results in the Alzheimer-like loss of brain cells.
Carol A. Colton, Ph.D., and colleagues recently developed a mouse model that carries a mutated human gene that results in the overproduction of beta-amyloid. This model is also missing the mouse gene that is essential for the production of nitric oxide. Nitric oxide plays a role in maintaining an appropriate chemical balance during cellular events.
As expected these mice developed beta-amyloid aggregates in the brain, but they also developed the Alzheimer-like tau pathology and experienced cell loss. This finding suggests a protective role for nitric oxide and may indicate the mechanism by which beta-amyloid pathology may be linked to tau pathology.
In this study, the researchers will examine mouse brains and assess the memories of the mice at different ages — or at different stages of disease progression — in order to determine the sequence of pathological events. They will also assess the effect of nitric oxide "treatment" on disease progression. The outcome of this work may elucidate not only the role of nitric oxide but also the link between beta-amyloid and tau pathologies.