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J. Biol. Chem., Vol. 281, Issue 47, 36180-36186, November 24, 2006

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Apolipoprotein E and Low Density Lipoprotein Receptor-related Protein Facilitate Intraneuronal A42 Accumulation in Amyloid Model Mice^*

Celina V. Zerbinatti, Suzanne E. Wahrle, Hyungjin Kim, Judy A. Cam, Kelly Bales^¶, Steven M. Paul^¶, David M. Holtzman^||, and Guojun Bu^**1

From the Departments of Pediatrics, Neurology, ^||Molecular Biology and Pharmacology, and ^**Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri 63110 and ^¶Neuroscience Discovery Research, Lilly Research Laboratories, Indianapolis, Indiana 46285

The low density lipoprotein receptor-related protein (LRP) is highly expressed in the brain and has been shown to alter the metabolism of amyloid precursor protein and amyloid- peptide (A) in vitro. Previously we developed mice that overexpress a functional LRP minireceptor (mLRP2) in their brains and crossed them to the PDAPP mouse model of Alzheimer disease. Overexpression of mLRP2 in 22-month-old PDAPP mice with amyloid plaques increased a pool of carbonate-soluble A in the brain and worsened memory-related behavior. In the current study, we examined the effects of mLRP2 overexpression on 3-month-old PDAPP mice that had not yet developed amyloid plaques. We found significantly higher levels of membrane-associated A42 in the hippocampus of mice that overexpressed mLRP2. Using immunohistochemical methods, we observed significant intraneuronal A42 in the hippocampus and frontal cortex of PDAPP mice, which frequently co-localized with the lysosomal marker LAMP-1. Interestingly, PDAPP mice lacking apolipoprotein E (apoE) had much less intraneuronal A42. We also found that PC12 cells overexpressing mLRP2 cleared A42 and A40 more rapidly from media than PC12 cells transfected with the vector only. Preincubation of apoE3 or apoE4 with A42 increased the rate of A clearance, and this effect was partially blocked by receptor-associated protein. Our results support the hypothesis that LRP binds and endocytoses A42 both directly and via apoE but that endocytosed A42 is not completely degraded and accumulates in intraneuronal lysosomes.

Received for publication, May 9, 2006 , and in revised form, September 18, 2006.

^* This work was supported by National Institutes of Health Grants F32-NS41872 (to C. V. Z.) and R01-AG027924 (to G. B.) and a grant from the Alzheimer Association (to G. B.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Campus Box 8208, 660 S. Euclid Ave., Saint Louis, MO 63110. Tel.: 314-286-2871; Fax: 314-286-2894; E-mail: bu{at}wustl.edu.

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