Harris-White Marni E, Balverde Zerlinde, Lim Giselle P, Kim Peter, Miller Sheryl A, Hammer Heidi, Galasko Doug, Frautschy Sally A
Department of Medicine, University of California, Los Angeles, California 91343, USA.
J Neurosci Res. 2004 Jul 15;77(2):217-28. doi: 10.1002/jnr.20149.
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.
越来越多的证据表明，可溶性淀粉样β肽（Aβ）被神经元摄取是阿尔茨海默病（AD）发病机制中的早期事件。确定导致神经元功能障碍的早期事件是制定治疗策略的关键，但对调节摄取的受体和因子的相对作用了解甚少。研究表明，转化生长因子β（TGFβ），尤其是TGFβ2，在体外可影响Aβ靶向细胞。TGFβ2可在器官型海马脑片培养（OHSC）中将Aβ靶向神经元。我们研究了TGFβ2介导的Aβ靶向神经元的具体机制。受体相关蛋白（RAP）是一种低密度脂蛋白受体相关蛋白（LRP）拮抗剂，在体外和体内均可减弱Aβ的细胞靶向作用，并预防Aβ/TGFβ2诱导的记忆保持缺陷。通过体外和体内方法，我们确定LRP在TGFβ2介导的Aβ摄取、神经退行性变和空间记忆损害中发挥作用。
