Published Online
on September 30, 2004

A more recent version of this article appeared on November 1, 2004

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Submitted on July 12, 2004
Revised on July 12, 2004
Accepted on August 5, 2004

RAGE (Yin) Versus LRP (Yang) Balance Regulates Alzheimer Amyloid -Peptide Clearance Through Transport Across the Blood-Brain Barrier

Rashid Deane PhD; Zhenhua Wu; and Berislav V. Zlokovic MD, PhD^*

From the Frank P Smith Laboratories for Neuroscience and Neurosurgical Research, Department of Neurological Surgery and Division of Neurovascular Biology, University of Rochester Medical Center, Rochester, NY.

^* To whom correspondence should be addressed. E-mail: berislav_zlokovic{at}urmc.rochester.edu.

Abstract--Accumulation of amyloid -peptide (A) in the central nervous system (CNS) may initiate pathogenic cascades mediating neurovascular and neuronal dysfunctions associated with the development of cerebral -amyloidosis and cognitive decline in patients with Alzheimer disease (AD) and with related familial cerebrovascular disorders. Whether A-related pathology in the CNS is reversible or not and what key therapeutic targets are controlling A/amyloid levels in the aging brain remain debatable. In this article, we summarize recent evidence why the receptor for advanced glycation end products and low-density lipoprotein receptor related protein 1 in the vascular CNS barriers are critical for regulation of A homeostasis in the CNS and how altered activities in these 2 receptors at the blood-brain barrier may contribute to the CNS A accumulation resulting in neuroinflammation, disconnect between the cerebral blood flow and metabolism, altered synaptic transmission, neuronal injury, and amyloid deposition into parenchymal and neurovascular lesions. We briefly discuss the potential of advanced glycation end products and low-density lipoprotein receptor related protein 1-based therapeutic strategies to control brain A in animal models of AD and ultimately in patients with AD and related familial cerebrovascular -amyloidoses.

Key words: acute care • Alzheimer disease • amyloid -protein • blood-brain barrier

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