Authors: Deane, R.; Sagare, A.; Zlokovic, B. V.

Source: Current Pharmaceutical Design, Volume 14, Number 16, June 2008 , pp. 1601-1605(5)

Publisher: Bentham Science Publishers

Abstract:

Low-density lipoprotein receptor related protein-1 (LRP) is a member of the low-density lipoprotein (LDL) receptor family which has been linked to Alzheimer's disease (AD) by biochemical and genetic evidence. Levels of neurotoxic amyloid β-peptide (Aβ) in the brain are elevated in AD contributing to the disease process and neuropathology. Faulty Aβ clearance from the brain appears to mediate focal Aβ accumulations in AD. Central and peripheral production of Aβ from Aβ-precursor protein (APP), transport of peripheral Aβ into the brain across the blood-brain barrier (BBB) via receptor for advanced glycation end products (RAGE), enzymatic Aβ degradation, Aβ oligomerization and aggregation, neuroinflammatory changes and microglia activation, and Aβ elimination from brain across the BBB by cell surface LRP; all may control brain Aβ levels. Recently, we have shown that a soluble form of LRP (sLRP) binds 70 to 90 % of plasma Aβ, preventing its access to the brain. In AD individuals, the levels of LRP at the BBB are reduced, as are levels of Aβ binding to sLRP in plasma. This, in turn, may increase Aβ brain levels through a decreased efflux of brain Aβ at the BBB and/or reduced sequestration of plasma Aβ associated with re-entry of free Aβ into the brain via RAGE. Thus, therapies which increase LRP expression at the BBB and/or enhance the peripheral Aβ “sink” activity of sLRP, hold potential to control brain Aβ accumulations, neuroinflammation and cerebral blood flow reductions in AD.

Keywords: LRP; sLRP; blood-brain barrier; Alzheimer's disease; Aβ clearance

Document Type: Research article

DOI: http://dx.doi.org/10.2174/138161208784705487

Affiliations: 1: Arthur Kornberg Medical Research Building, University of Rochester Medical Center, 601 Elmwood Avenue, Box 645, Rochester, NY 14642, USA.

Publication date: 2008-06-01

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  Each thematic issue of Current Pharmaceutical Design covers all subject areas of major importance to modern drug design, including: medicinal chemistry, pharmacology, drug targets and disease mechanism.

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