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.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Pilot Research Project (SC2)
Project #
Application #
Study Section
Special Emphasis Panel (ZGM1)
Program Officer
Corriveau, Roderick A
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
North Carolina Agri & Tech State University
Engineering (All Types)
Biomed Engr/Col Engr/Engr Sta
United States
Zip Code
Ma, Jun; Zhao, Nan; Zhu, Donghui (2015) Sirolimus-eluting dextran and polyglutamic acid hybrid coatings on AZ31 for stent applications. J Biomater Appl 30:579-88
Zhu, Donghui; Bungart, Brittani L; Yang, Xiaoguang et al. (2015) Role of membrane biophysics in Alzheimer's-related cell pathways. Front Neurosci 9:186
Zhao, Nan; Zhu, Donghui (2015) Endothelial responses of magnesium and other alloying elements in magnesium-based stent materials. Metallomics 7:118-28
Zhao, Zhen; Sagare, Abhay P; Ma, Qingyi et al. (2015) Central role for PICALM in amyloid-? blood-brain barrier transcytosis and clearance. Nat Neurosci 18:978-87
Zhao, Nan; Zhu, Donghui (2014) Collagen self-assembly on orthopedic magnesium biomaterials surface and subsequent bone cell attachment. PLoS One 9:e110420
Zhao, Nan; Workman, Benjamin; Zhu, Donghui (2014) Endothelialization of novel magnesium-rare earth alloys with fluoride and collagen coating. Int J Mol Sci 15:5263-76
Zhao, Nan; Watson, Nevija; Xu, Zhigang et al. (2014) In vitro biocompatibility and endothelialization of novel magnesium-rare Earth alloys for improved stent applications. PLoS One 9:e98674
Ma, Jun; Thompson, Marc; Zhao, Nan et al. (2014) Similarities and differences in coatings for magnesium-based stents and orthopaedic implants. J Orthop Translat 2:118-130