Role of LRP in TGFbeta2-mediated neuronal uptake of Abeta and effects on memory.
There is increasing evidence that soluble amyloid-beta peptide (Abeta) uptake into neurons is an early event in the pathogenesis of Alzheimer's disease (AD). Identification of the early events leading to neuronal dysfunction is key to developing therapeutic strategies, but relative roles of receptors and factors modulating uptake are poorly understood. Studies have shown that transforming growth factor beta (TGFbeta), particularly TGFbeta2, can influence the targeting of Abeta to cells in vitro. TGFbeta2 can target Abeta to neurons in organotypic hippocampal slice cultures (OHSC). We examine a specific mechanism for TGFbeta2-mediated targeting of Abeta to neurons. The receptor-associated protein (RAP), a low-density lipoprotein receptor-related protein (LRP) antagonist, can attenuate the cellular targeting of Abeta both in vitro and in vivo and prevent Abeta/TGFbeta2-induced memory retention deficits. Using both in vitro and in vivo methods, we identify LRP as playing a role in TGFbeta2-mediated Abeta uptake, neurodegeneration, and spatial memory impairment.
Harris-White
Marni E
ME
Department of Medicine, University of California, Los Angeles, California 91343, USA. marni@ucla.edu
Balverde
Zerlinde
Z
Lim
Giselle P
GP
Kim
Peter
P
Miller
Sheryl A
SA
Hammer
Heidi
H
Galasko
Doug
D
Frautschy
Sally A
SA
D000544:Alzheimer Disease / Q000378:metabolism / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D006624:Hippocampus / Q000378:metabolism* / Q000503:physiopathology; D066298:In Vitro Techniques; D026563:LDL-Receptor Related Protein-Associated Protein / Q000378:metabolism / Q000494:pharmacology; D026503:Low Density Lipoprotein Receptor-Related Protein-1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008569:Memory Disorders / Q000378:metabolism* / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D009410:Nerve Degeneration / Q000378:metabolism / Q000503:physiopathology; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D021381:Protein Transport / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D053781:Transforming Growth Factor beta2
D016229:Amyloid beta-Peptides; D026563:LDL-Receptor Related Protein-Associated Protein; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D016212:Transforming Growth Factor beta; D053781:Transforming Growth Factor beta2