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The Journal of Neuroscience, November 1, 2002, 22(21):9298-9304

Increased Extracellular Amyloid Deposition and Neurodegeneration in Human Amyloid Precursor Protein Transgenic Mice Deficient in Receptor-Associated Protein

Emily Van Uden¹, Margaret Mallory¹, Isaac Veinbergs¹, Michael Alford¹, Edward Rockenstein¹, and Eliezer Masliah^{1, 2}

Departments of ¹ Neurosciences and ² Pathology, University of California, San Diego, School of Medicine, La Jolla, California 92093-0624

The low-density lipoprotein receptor-related protein (LRP) is an abundant neuronal cell surface receptor that regulates amyloid -protein (A) trafficking into the cell. Specifically, LRP binds secreted A complexes and mediates its degradation. Previously, we have shown in vitro that the uptake of A mediated by LRP is protective and that blocking this receptor significantly enhances neurotoxicity. To further characterize the effects of LRP and other lipoprotein receptors on A deposition, an in vivo model of decreased LRP expression, receptor-associated protein (RAP)-deficient (RAP/) mice was crossed with human amyloid protein precursor transgenic (hAPP tg) mice, and plaque formation and neurodegeneration were analyzed. We found that, although the age of onset for plaque formation was the same in hAPP tg and hAPP tg/RAP/ mice, the amount of amyloid deposited doubled in the hAPP tg/RAP/ background. Moreover, these mice displayed increased neuronal damage and astrogliosis. Together, these results further support the contention that LRP and other lipoprotein receptors might be neuroprotective against A toxicity and that this receptor might play an integral role in A clearance.

Key words: amyloid  protein; amyloid precursor protein; apopoliprotein E; low-density lipoprotein receptor; receptor-associated protein; transgenic mice

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Copyright © 2002 Society for Neuroscience  0270-6474/02/22219298-07$05.00/0

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