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ALzheimer's disease, ApoE, APP, Abeta, LRP, endocytosis, receptor sorting
Our laboratory is interested in the cell biology of intracellular protein trafficking. Our studies have been focused primarily on a large endocytic receptor, the low-density lipoprotein receptor (LDLR)-related protein (LRP). LRP is a multifunctional cell surface receptor, capable of binding and endocytosing over 30 ligands. We are interested in identifying both trans- and cis-elements within the cytoplasmic tail of LRP that govern its trafficking and signaling. Three LRP ligands, apolipoprotein E (apoE), amyloid precursor protein (APP) and amyloid-beta peptide (Abeta) have been shown to participate in the pathogenesis of Alzheimer’s disease (AD). Mounting evidence has shown that brain Abeta accumulation could be causal to the pathogenesis of AD. Therefore understanding the mechanism of Abeta production and metabolism is crucial to the development of therapeutic strategies to combat AD. Abeta is derived from proteolytic processing of APP, which interacts with several members of the LDLR family. Studies from our laboratory have utilized both in vitro and in vivo models to understand the roles of LDLR family members in Abeta metabolism by focusing on three members: LRP, LRP1B and the LDLR. Our in vitro cellular studies have shown that while LRP’s rapid endocytosis facilitates APP endocytic trafficking and processing to Abeta, LRP1B’s slow endocytosis inhibits these processes. Our recent studies have also identified a novel APP-interacting protein, sorting nexin 17 (SNX17), which recognizes a tyrosine-containing motif in the cytoplasmic tail of APP and modulates its endocytic recycling and processing to Abeta. In addition to modulating APP endocytic trafficking, LRP’s rapid endocytosis also facilitates Abeta cellular uptake by binding to Abeta either directly or via LRP ligands such as apoE. Our in vivo studies using transgenic approach have shown that overexpression of LRP in CNS neurons increases cell-associated Abeta and this increase correlates with an enhanced memory deficits in mice. We are currently investigating the cellular mechanisms by which LRP facilitates intraneuronal Abeta accumulation, a pathological event that directly contributes to the early cognitive deficits seen in AD. Our preliminary results indicate that apoE plays an important role in intraneuronal Abeta accumulation, likely by shuttling Abeta into neurons via LRP-mediated pathways. Our long term goal in AD research is to understand how LRP expression and function are dysregulated during aging and AD and how these events in turn impact the metabolism and function of apoE/lipoprotein and Abeta.

Research Photos (Click to Enlarge)

Research Publications

Zerbinatti CV, Wahrle SE, Kim H, Cam JA, Bales K, Paul SM, Holtzman DM, Bu G (2006 Nov 24). Apolipoprotein E and low density lipoprotein receptor-related protein facilitate intraneuronal Abeta42 accumulation in amyloid model mice. J Biol Chem. 281 (47): 36180-6. Full Article >

van Kerkhof P, Lee J, McCormick L, Tetrault E, Lu W, Schoenfish M, Oorschot V, Strous GJ, Klumperman J, Bu G (2005 Aug 17). Sorting nexin 17 facilitates LRP recycling in the early endosome. EMBO J. 24 (16): 2851-61. Full Article >

Cam JA, Zerbinatti CV, Li Y, Bu G (2005 Apr 15). Rapid endocytosis of the low density lipoprotein receptor-related protein modulates cell surface distribution and processing of the beta-amyloid precursor protein. J Biol Chem. 280 (15): 15464-70. Full Article >

Zerbinatti CV, Wozniak DF, Cirrito J, Cam JA, Osaka H, Bales KR, Zhuo M, Paul SM, Holtzman DM, Bu G (2004 Jan 27). Increased soluble amyloid-beta peptide and memory deficits in amyloid model mice overexpressing the low-density lipoprotein receptor-related protein. Proc Natl Acad Sci U S A. 101 (4): 1075-80. Full Article >

Marzolo MP, Yuseff MI, Retamal C, Donoso M, Ezquer F, Farfan P, Li Y, Bu G (2003 Apr). Differential distribution of low-density lipoprotein-receptor-related protein (LRP) and megalin in polarized epithelial cells is determined by their cytoplasmic domains. Traffic. 4 (4): 273-88. Full Article >

Melman L, Geuze HJ, Li Y, McCormick LM, Van Kerkhof P, Strous GJ, Schwartz AL, Bu G (2002 Sep). Proteasome regulates the delivery of LDL receptor-related protein into the degradation pathway. Mol Biol Cell. 13 (9): 3325-35. Full Article >

Contact Info
Guojun Bu, Ph.D.
Office Location: 5104 MPRB
Office Phone: 314-286-2860
Lab Phone: 314-286-2871
Campus Box: 8208
Fax: 314-286-2894

bu@kids.wustl.edu
http://bulab.wustl.edu/