Project 171047

Alzheimer's disease (AD) is known to affect the blood vessels in the brain. Growing evidence points to the fact that abnormalities of the blood vessels play a major role in the development and progression of AD. As such, new drugs which target AD-associated changes in blood vessels represent an exciting and very promising avenue of development for prevention and/or reversal of disease. The ability to determine the effectiveness of these new drugs at an early stage of development is critical to ensuring that only promising agents are moved ahead to further stages of testing. In this proposal, we plan to develop and evaluate cutting-edge methods to improve our understanding of blood vessel ('vascular') disease. These studies will be performed on 'transgenic' mice, which have been genetically-modified to develop AD-type brain and vascular disease. The methods that we will utilize include memory testing experiments and non-invasive magnetic resonance imaging (MRI) studies of vascular function in the brains of live animals, as well as state-of-the-art techniques for examining vascular disease on post-mortem brain tissue. For the post-mortem studies, we have developed sophisticated methods of measuring very specific disease-related changes in three-dimensions (3D). We have developed a new technology for producing detailed, quantitative images of the microscopic changes which are known to occur during the development of AD. These 3D post-mortem studies will provide complementary information to the data obtained from live animals, and allow us to create a more complete picture of the development of vascular disease and the manner in which it relates to the progression of AD.

integrating in vivo MRI and ex vivo quantitative immunohistochemistry to characterize cerebrovascular dysfunction in transgenic models of Alzheimer's disease