Brain Pericyte and Amyloid-beta Peptide Interaction

描述（由申请人提供）：周细胞是位于脑微血管外的小细胞，位于内皮细胞层和实质之间。周细胞作为神经血管单元的一部分，除了有助于血脑屏障（BBB）维持和止血外，还具有广泛的功能，包括收缩、免疫、吞噬和干细胞功能。阿尔茨海默病（AD）的一个病理标志是血脑屏障受损，其特征是内皮细胞外壁周细胞显著减少。内皮上的周细胞覆盖是血脑屏障正常功能所必需的，这些细胞的破坏与AD症状的发生和进展之间的关系目前尚不清楚。了解周细胞功能在AD等病理条件下的意义将导致未来药物干预和改进治疗的发展。本研究的目的是了解在退行性疾病（如阿尔茨海默病）中导致内皮壁上周细胞覆盖减少和血脑屏障减弱的机制和过程。目的1是确定A¿是否降低PDGFR¿和参与周细胞介导的血脑屏障完整性调节的信号分子，导致AD患者血脑屏障受损。如果PDGFR¿控制周细胞向血管壁的募集，那么A¿诱导的PDGFR¿表达降低将有助于解释AD内皮壁外周细胞募集的损失或受损。

DESCRIPTION (provided by applicant): 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.