Zhuo M, Holtzman D M, Li Y, Osaka H, DeMaro J, Jacquin M, Bu G
Department of Anesthesiology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
J Neurosci. 2000 Jan 15;20(2):542-9. doi: 10.1523/JNEUROSCI.20-02-00542.2000.
The low-density lipoprotein (LDL) receptor-related protein (LRP) is a multifunctional endocytic receptor that is expressed abundantly in neurons of the CNS. Both LRP and several of its ligands, including tissue plasminogen activator (tPA), apolipoprotein E/lipoproteins, alpha(2)-macroglobulin, and the beta-amyloid precursor protein, have been implicated in various neuronal functions and in the pathogenesis of Alzheimer's disease. It has been reported that induction of tPA expression may contribute to activity-dependent synaptic plasticity in the hippocampus and cerebellum. In addition, long-term potentiation (LTP) is significantly decreased in mice lacking tPA. Here we demonstrate that tPA receptor LRP is abundantly expressed in hippocampal neurons and participates in hippocampal LTP. Perfusion of hippocampal slices with receptor-associated protein (RAP), an antagonist for ligand interactions with LRP, significantly reduced late-phase LTP (L-LTP). In addition, RAP also blocked the enhancing effect of synaptic potentiation by exogenous tPA in hippocampal slices prepared from tPA knock-out mice. Metabolic labeling and ligand binding analyses showed that both tPA and LRP are synthesized by hippocampal neurons and that LRP is the major cell surface receptor that binds tPA. Finally, we found that tPA binding to LRP in hippocampal neurons enhances the activity of cyclic AMP-dependent protein kinase, a key molecule that is known to be involved in L-LTP. Taken together, our results demonstrate that interactions between tPA and cell surface LRP are important for hippocampal L-LTP.
低密度脂蛋白（LDL）受体相关蛋白（LRP）是一种多功能内吞受体，在中枢神经系统的神经元中大量表达。LRP及其几种配体，包括组织纤溶酶原激活物（tPA）、载脂蛋白E/脂蛋白、α2巨球蛋白和β淀粉样前体蛋白，都与各种神经元功能以及阿尔茨海默病的发病机制有关。据报道，tPA表达的诱导可能有助于海马体和小脑中依赖活动的突触可塑性。此外，在缺乏tPA的小鼠中，长时程增强（LTP）显著降低。在这里，我们证明tPA受体LRP在海马神经元中大量表达，并参与海马LTP。用受体相关蛋白（RAP）灌注海马切片，RAP是一种与LRP配体相互作用的拮抗剂，可显著降低晚期LTP（L-LTP）。此外，RAP还阻断了外源性tPA对tPA基因敲除小鼠制备的海马切片中突触增强的促进作用。代谢标记和配体结合分析表明，tPA和LRP均由海马神经元合成，且LRP是结合tPA的主要细胞表面受体。最后，我们发现tPA与海马神经元中的LRP结合可增强环磷酸腺苷依赖性蛋白激酶的活性，该关键分子已知参与L-LTP。综上所述，我们的结果表明tPA与细胞表面LRP之间的相互作用对海马L-LTP很重要。
