Late onset cognitive decline is likely to be caused by a mixture of pathological processes. Clinical, neuropathological and epidemiological studies suggest that late onset cognitive decline is likely to be linked with microvascular factors. Microvascular pathology has been less studied as a potential mechanism of cognitive decline, perhaps because of difficulties in investigating it in humans due to a lack of tools for imaging microvessels at high resolution in vivo. Thus, there is still no clear understanding as to how the potential synergism between vascular and Alzheimer's pathologies might occur. We have previously discovered a novel mechanism of microvascular recanalization, termed angiophagy, involving the engulfment of emboli by the endothelium followed by their translocation through the vessel wall into the perivascular space leading to flow reestablishment. We propose the novel hypothesis that this mechanism of recanalization plays a critical role in the interactions between microvascular and Alzheimer's pathologies. To test these hypothesis we have developed sophisticated and sensitive experimental methods, combining an Alzheimer's mouse model with our fluorescent microembolization technique, high-resolution in vivo and fixed tissue imaging of emboli and vessels, and fluorescent nanoparticle labeling of clots for long term-tracking in fixed tissues. These set of experiments will greatly improve our understanding of the potential interactions between microvascular occlusion and cerebral amyloid angiopathy a potential critical link between these prevalent conditions. Our proposed work will determine whether there is a vicious cycle between microvascular abnormalities and AD pathology, providing critical novel avenues for therapy development.

Public Health Relevance

Clinical, neuropathological and epidemiological studies suggest that late onset cognitive decline is likely to be linked with microvascular factors. We have previously discovered a novel mechanism of microvascular recanalization, termed angiophagy, involving the engulfment of emboli by the endothelium followed by their translocation through the vessel wall into the perivascular space leading to flow reestablishment. This application proposes to explore the interaction between angiophagy process and amyloid deposition, a hall mark in Alzheimer's disease. The proposed research would provide fundamental insights about the complex interaction of the diverse pathological factors occurring in aging which contribute to cognitive decline.

Agency
National Institute of Health (NIH)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21AG048181-01
Application #
8754551
Study Section
Cell Death and Injury in Neurodegeneration Study Section (CDIN)
Program Officer
Petanceska, Suzana
Project Start
Project End
Budget Start
Budget End
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Yale University
Department
Neurology
Type
Schools of Medicine
DUNS #
City
New Haven
State
CT
Country
United States
Zip Code
06510