LRP in amyloid-beta production and metabolism.
Amyloid-beta peptide (Abeta) production and accumulation in the brain is a central event in the pathogenesis of Alzheimer's disease (AD). Recent studies have shown that apolipoprotein E (apoE) receptors, members of the low-density lipoprotein receptor (LDLR) family, modulate Abeta production as well as Abeta cellular uptake. Abeta is derived from proteolytic processing of the amyloid precursor protein (APP), which interacts with several members of the LDLR family. Studies from our laboratory have focused on two members of the LDLR family, the LDLR-related protein (LRP) and LRP1B. Our in vitro studies have shown that while LRP's rapid endocytosis facilitates APP endocytic trafficking and processing to Abeta, LRP1B's slow endocytosis inhibits these processes. 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 mice have shown that overexpression of LRP in central nervous system (CNS) neurons increases soluble brain Abeta and this increase correlates with deficits in memory. Together our studies demonstrate that members of the LDLR family modulate APP processing and Abeta metabolism by several independent mechanisms. Understanding the pathways that modulate brain Abeta metabolism may enable the rational design of molecular medicine to treat AD.
Bu
Guojun
G
Department of Pediatrics, Washington University School of Medicine, 660 South Euclid Avenue, CB 8208, St. Louis, MO 63110, USA. bu@wustl.edu
Cam
Judy
J
Zerbinatti
Celina
C
D000544:Alzheimer Disease / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000096:biosynthesis / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000378:metabolism*; D004705:Endocytosis / Q000502:physiology; D011992:Endosomes / Q000378:metabolism; D006801:Humans; D026502:LDL-Receptor Related Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D026502:LDL-Receptor Related Proteins; C434476:LRP1B protein, human; C486644:Lrp1b protein, mouse; D011973:Receptors, LDL; D025521:Tumor Suppressor Proteins