Relating Vascular Pathology to Memory Deficits in APP Overexpressing Mice

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that causes memory loss as well as impairments to judgment and decision making. This project examined the relationship between cerebral blood flow, cerebral vascularity, neurodegeneration, and memory in a mouse model of Alzheimer's disease. The work was motivated by the amyloid cascade hypothesis: that an excess of the amyloid-beta amino acid peptide causes a cascade of events leading to Alzheimer's disease. Reduced clearance of amyloid-beta into the blood circulation is one of the proposed mechanisms by which this excess could arise and is supported by evidence of hypoperfusion and impaired cerebral blood flow regulation in patients with Alzheimer's disease. Our study examined this clearance hypothesis by assessing whether impaired blood flow is necessary for memory impairments to occur. Our approach to this problem was to use 3D imaging and genetically engineered mice that reproduce many of the features of the amyloid cascade. Specifically these mice show amyloid plaques, a hallmark of Alzheimer's disease, abnormal blood vessels, and most importantly, memory impairments. The mice were examined by magnetic resonance imaging (MRI), X-ray computed tomography (similar to a hospital CAT scan), laser Doppler flowmetry, and subsequently by histology. We collaborated on this project with Dr. Edith Hamel an established expert on cerebral vascular function who is based at the Montreal Neurological Institute. Laser Doppler measurements were conducted in Montreal while MRI and X-ray imaging were conducted at MICe. An initial paper based on this work is in preparation.

Research is funded by the Alzheimer's Association USA