Exploring the function of stalled capillary flow as a novel mechanism for hypoperfusion in Alzheimer disease

• Applicant: Dr. Oliver Bracko, Ph.D.
• Subject Area: Molecular and Cellular Neurology and Neuropathology
• Term: from 2015 to 2017
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 282897701

Alzheimer disease (AD) is the most common form of dementia and accounts for about 60-80% of all cases. AD typically begins with slight but progressive failure of memory and slowly becomes more severe, eventually leading to a profound memory loss. AD is a complex disease characterized by an accumulation of amyloid-beta (Abeta) plaques and neurofibrillary tangles composed of tau which are eventually associated with synapse loss and neurodegeneration. In AD, vascular pathology seems to interact with neurodegeneration and therefore contributes to disease progression. However, this relationship is poorly understood but new findings strengthen the importance of the vascular contribution to neurodegenerative diseases. Interestingly, research in humans and animals suggests that in AD brain blood flow is reduced by ~30%. Although this hypoperfusion likely contributes to cognitive impairment and disease progression, no physiological explanation has emerged. Chronic in vivo two photon excited fluorescence microscopy was used to study cerebrovascular blood flow (CBF) in mouse models of AD. While no blood flow disruption in cortical arterioles or venules was observed, blood flow was found to be stalled in an average of 1.8% of cortical capillaries in mouse models of AD, as compared to 0.25% in wild type controls (p<0.005; data from Schaffer-Nishimura lab). These capillary stalls appeared early in disease progression, before any amyloid deposition. Because one stalled capillary reduces flow in several downstream vessels, even only ~2% of capillaries stalled could have a large impact on brain blood flow. Indeed, when leukocytes were depleted in AD mice and the fraction of capillary stalls dropped to near zero, brain blood flow improved by ~30%, suggesting that capillary stalling may cause brain hypoperfusion in AD. This blood flow deficit could contribute to dementia independently of the direct effects of Abeta and could also accelerate Abeta aggregation by decreasing clearance of Abeta monomers. In the proposed research project we will analyze the effect of releasing capillary stalls in mouse models of AD by testing three hypotheses: First, analyze early time points in a AD mouse model to determine if capillary stalls are an early feature in disease progression. Second, perform behavioral experiments to determine if eliminating capillary stalls have an immediate effect on cognition due to an increase in blood flow. Third, analyze the long-term effects of eliminating capillary plugs and determine if increasing blood flow will lead to an improvement in cognitive performance and a decreased amyloid burden. The hypothesis that brain hypoperfusion in AD is due to leukocyte plugging in capillaries is novel, yet supported by data from my host lab, and could directly suggest therapeutic targets that are complementary to anti-amyloid approaches.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professor Dr. Chris Schaffer