Abstract

This proposal represents investigators from the University of Southern California, Columbia University and State University of New York at Stony Brook Schools of Medicine who participate in a multi-disciplinary program on Cerebrovascular Mechanisms in the Aging Brain. The goal of the program is to advance current knowledge regarding the role of vasculature in the aging brain and major CNS disorders in elderly that predispose to cerebrovascular amyloidosis (e.g., Alzheimer's Disease and related amyloid-beta-peptide (Abeta) disorders, such as hereditary cerebral hemorrhage with amyloidosis Dutch type), Abeta-related vascular injury, brain damage and stroke. We will apply concepts and techniques developed in cerebrovascular biology, blood-brain barrier (BBB) and cerebrospinal fluid physiology, molecular biology, molecular genetics, transgene mice with age-dependent vascular risk factors, and tissues and cell cultures from patients diagnosed with AD. The program consists of five Research Projects and three Core resources. Project 1, Dr. Zlokovic will study the role of BBB and brain clearance in regulating Abeta concentrations in cerebral vessel wall and brain. Project the role of BBB and brain clearance in regulating Abeta concentrations in cerebral vessel wall and brain. Project 2, Dr. Van Nostrand will study Abeta production by cerebrovascular smooth muscle cells in relation to amyloidosis. Project, Dr. Stern will study the role of receptor for advanced glycation and end products in acute and chronic cerebrovascular perturbation caused by Abeta and stroke-risk factors. Project 44, Drs. Schreiber and Zlokovic will delineate the roles of Abeta dn amyloid in vascular hemostasis in relation to ischemic or hemorrhagic stroke. Project 5, Drs. Kalra and Rhodin will study the role of Abeta in migration of monocytes across the BBB and vascular wall. Core A is the administrative facility. Core B, Dr. Mackic and Kim will provide animal and cell culture facility. Core C, Dr. Miller will provide neuropathologic analysis. The integrated and complementary scientific research projects will provide a molecular and therapeutic rationale to prevent accumulation of Abeta and formation of amyloid in cerebral blood vessels and brain, and counteract age-dependent mechanisms responsible for abnormal vascular responses, injury and brain damage.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program Projects (P01)
Project #
5P01AG016223-04
Application #
6509764
Study Section
National Institute on Aging Initial Review Group (NIA)
Program Officer
Snyder, Stephen D
Project Start
1999-05-01
Project End
2004-04-30
Budget Start
2002-05-01
Budget End
2003-04-30
Support Year
4
Fiscal Year
2002
Total Cost
$1,026,910
Indirect Cost

  Institution

Name
University of Rochester
Department
Neurosurgery
Type
Schools of Dentistry
DUNS #
208469486
City
Rochester
State
NY
Country
United States
Zip Code
14627

  Publications

LaRue, Barbra; Hogg, Elizabeth; Sagare, Abhay et al. (2004) Method for measurement of the blood-brain barrier permeability in the perfused mouse brain: application to amyloid-beta peptide in wild type and Alzheimer's Tg2576 mice. J Neurosci Methods 138:233-42
Wu, Ed X; Tang, Haiying; Asai, Tomohiro et al. (2004) Regional cerebral blood volume reduction in transgenic mutant APP (V717F, K670N/M671L) mice. Neurosci Lett 365:223-7
Zlokovic, Berislav V (2004) Clearing amyloid through the blood-brain barrier. J Neurochem 89:807-11
Arancio, Ottavio; Zhang, Hui Ping; Chen, Xi et al. (2004) RAGE potentiates Abeta-induced perturbation of neuronal function in transgenic mice. EMBO J 23:4096-105
Deane, Rashid; Zheng, Wei; Zlokovic, Berislav V (2004) Brain capillary endothelium and choroid plexus epithelium regulate transport of transferrin-bound and free iron into the rat brain. J Neurochem 88:813-20
Deane, Rashid; Wu, Zhenhua; Sagare, Abhay et al. (2004) LRP/amyloid beta-peptide interaction mediates differential brain efflux of Abeta isoforms. Neuron 43:333-44
Deane, Rashid; Wu, Zhenhua; Zlokovic, Berislav V (2004) RAGE (yin) versus LRP (yang) balance regulates alzheimer amyloid beta-peptide clearance through transport across the blood-brain barrier. Stroke 35:2628-31
Tieu, Kim; Perier, Celine; Vila, Miquel et al. (2004) L-3-hydroxyacyl-CoA dehydrogenase II protects in a model of Parkinson's disease. Ann Neurol 56:51-60
Jung, Sonia S; Van Nostrand, William E (2003) Humanin rescues human cerebrovascular smooth muscle cells from Abeta-induced toxicity. J Neurochem 84:266-72
Wu, Zhenhua; Hofman, Florence M; Zlokovic, Berislav V (2003) A simple method for isolation and characterization of mouse brain microvascular endothelial cells. J Neurosci Methods 130:53-63

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