Authors: Moir, Robert D.; Tanzi, Rudolph E.

Source: Current Alzheimer Research, Volume 2, Number 2, April 2005 , pp. 269-273(5)

Publisher: Bentham Science Publishers

Abstract:

The pathogenesis of Alzheimer's disease (AD) involves the abnormal accumulation and deposition of - amyloid in cerebral blood vessels and in the brain parenchyma. Critical in modulating -amyloid deposition in brain is the flux of A across the blood brain barrier. The low-density lipoprotein receptor-related protein (LRP), is a large endocytic receptor that mediates the efflux of A out of brain and into the periphery. The first step in the LRP-mediated clearance of Ab involves the formation of a complex between A and the LRP ligands apolipoprotein E (apoE) or 2-macroglobulin (2M). The A / chaperone complexes then bind to LRP via binding sites on apoE or 2M. The efflux of A / chaperone complexes out of the neuropil and into the periphery may be attenuated by LRP-ligands that compete with apoE or 2M for LRP binding. LRP is also the cell surface receptor for Kunitz Protease Inhibitor (KPI) containing isoforms of Ab's parent protein, the amyloid protein precursor (APP). Protein and mRNA levels of KPI-containing APP isoforms (APP-KPI) are elevated in AD brain and are associated with increased Ab production. In this study we show that soluble non-amyloidogenic APP-KPI can also inhibit the uptake of A / 2M in a cell culture model of LRP mediated A clearance. Clearance of A / apoE complexes was not inhibited by APP-KPI. Our findings are consistent with studies showing that apoE and 2M have discrete binding sites on LRP. Most significantly, our data suggests that the elevated levels of APP-KPI in AD brain may attenuated the clearance of A, the proteins own amyloidogenic catabolic product.

Keywords: alzheimers disease; clearance; low density lipoprotein receptor-related protein; apolipoprotein e; macroglobulin; amyloid protein precursor

Document Type: Review article

DOI: http://dx.doi.org/10.2174/1567205053585918

Affiliations: 1: Genetics and Aging Research Unit, Building 114, 16th Street, Charlestown MA, 02129-4404, USA.

Publication date: 2005-04-01

More about this publication?

• Current Alzheimer Research publishes peer-reviewed frontier review and research articles on all areas of Alzheimer's disease. This multidisciplinary journal will help in understanding the neurobiology, genetics, pathogenesis, and treatment strategies of Alzheimer's disease. The journal publishes objective reviews written by experts and leaders actively engaged in research using cellular, molecular, and animal models. The journal also covers original articles on recent research in fast emerging areas of molecular diagnostics, brain imaging, drug development and discovery, and clinical aspects of Alzheimer's disease. Manuscripts are encouraged that relate to the synergistic mechanism of Alzheimer's disease with other dementia and neurodegenerative disorders. Book reviews, meeting reports and letters-to-the-editor are also published. The journal is essential reading for researchers, educators and physicians with interest in age-related dementia and Alzheimer's disease. Current Alzheimer Research provides a comprehensive 'bird's-eye view' of the current state of Alzheimer's research for neuroscientists, clinicians, health science planners, granting, caregivers and families of this devastating disease.

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