Pericytes are small cells located outside of brain microvessels between the endothelial cell layer and the parenchyma. As part of the neurovascular unit, pericytes have a substantial range of functions including contractile, immune, phagocytic and stem cell functions, in addition to contributing to blood-brain barrier (BBB) maintenance and hemostasis. One pathological hallmark of Alzheimer's disease (AD) is a compromised BBB characterized by significant reductions in pericytes on the exterior walls of endothelia. Pericyte coverage on endothelia is necessary for normal BBB functioning and the relationship between destruction of these cells and the development and progression of AD symptoms is currently not well understood. Understanding the significance of pericyte functioning in pathological conditions such as AD will lead to the development of future pharmaceutical interventions and improved treatment. The objective of this study is to understand the mechanisms and processes that lead to reduced coverage of pericytes on the endothelial wall and the resulting weakening of the BBB in degenerative conditions such as AD.
Aim 1 is to determine if A? decreases PDGFR? and signaling molecules involved in pericyte-mediated BBB integrity regulation, leading to a compromised BBB in AD. If PDGFR? controls the recruitment of pericytes to vessel wall, then reduced expression of PDGFR? induced by A? will help explain the loss or impaired recruitment of pericytes outside the endothelial wall in AD. If TGF?, VEGF, and angiopoietin-1/-2 maintain BBB tight junction and paracellular permeability, then decreased secretion of these molecules from pericytes by A? will reveal an additional unknown mechanism leading to the compromise and leaks of the BBB in AD. We will examine the expression and translocation of these molecules using RT-PCR, Western blot and quantitative imaging techniques.
Aim 2 is to determine if A? alters contractile and cytoskeletal proteins, therefore decreasing mobility, adhesion, and migration ability of pericytes, leading to impaired recruitment of pericytes to endothelia. Pericyte movement to endothelial cells is pivotal in vascular development and maintenance. Given that cytoskeletal and contratile proteins play key roles in cell shape, contraction, mobility and BBB permeability regulation, then our investigation of these proteins'expression, including alpha-smooth muscle actin (? -SMA) and myosin, and related actin cytoskeletal reorganization in the presence of A? will indicate that fewer pericytes are recruited to endothelia. Using in vitro capillary-like structures, we will idenify the rate-limiting step and key-signaling molecules in pericyte adhesion and migration affected by A?. The rate-limiting step would be the ideal target for therapies.

Public Health Relevance

This proposed project will significantly increase our understanding of the role of pericytes and pericyte-A? interaction in regulating and maintaining the integrity of the brain's microvascular system in pathological conditions such as Alzheimer's disease (AD). It will also provide useful information for the development of future pharmaceutical interventions targeting pericyte protection in the treatment of AD.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Pilot Research Project (SC2)
Project #
5SC2NS082475-02
Application #
8539524
Study Section
Special Emphasis Panel (ZGM1-MBRS-Y (SC))
Program Officer
Corriveau, Roderick A
Project Start
2012-09-01
Project End
2015-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
2
Fiscal Year
2013
Total Cost
$137,513
Indirect Cost
$41,013
Name
North Carolina Agri & Tech State University
Department
Engineering (All Types)
Type
Schools of Engineering
DUNS #
071576482
City
Greensboro
State
NC
Country
United States
Zip Code
27411