Lee R K, Jimenez J, Cox A J, Wurtman R J
Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge 02139, USA.
Ann N Y Acad Sci. 1996 Jan 17;777:338-43. doi: 10.1111/j.1749-6632.1996.tb34443.x.
It has previously been shown that stimulation of muscarinic m1 or m3 receptors can, by generating diacylglycerol (DAG) and activating protein kinase C (PKC), accelerate the breakdown of the amyloid precursor protein (APP) to form soluble, non-amyloidogenic peptides (APPs). This relationship has been demonstrated in human glioma and neuroblastoma cells as well as in transfected human embryonic kidney (HEK) cells and PC12 cells. We now provide evidence that stimulation of metabotropic glutamate receptors (mGluRs), which also are coupled to DAG and PKC, similarly accelerates processing of APP into non-amyloidogenic APPs in hippocampal neurons and cortical astrocytes derived from normal fetal rats. The mGluR antagonist, L(+)-2-amino-3-phosphonopropionic acid (L-AP3), and GF 109203X, an inhibitor of PKC, both blocked the release of APPs from hippocampal neurons and astrocytes evoked by glutamate receptor stimulation. Inasmuch as glutamatergic neurons in cortex and hippocampus are known to be damaged in Alzheimer's disease, our findings suggest that amyloid formation may be enhanced by the resulting glutamate deficiency and that selective mGluR agonists may be useful in facilitating synaptic efficacy and treating the disease.
先前的研究表明，刺激毒蕈碱型m1或m3受体，通过生成二酰基甘油（DAG）并激活蛋白激酶C（PKC），可加速淀粉样前体蛋白（APP）的分解，以形成可溶性、非淀粉样生成性肽（APPs）。这种关系已在人胶质瘤和神经母细胞瘤细胞以及转染的人胚肾（HEK）细胞和PC12细胞中得到证实。我们现在提供证据表明，刺激同样与DAG和PKC偶联的代谢型谷氨酸受体（mGluRs），同样能加速正常胎鼠来源的海马神经元和皮质星形胶质细胞中APP加工成非淀粉样生成性APPs的过程。mGluR拮抗剂L(+)-2-氨基-3-膦丙酸（L-AP3）和PKC抑制剂GF 109203X，均能阻断谷氨酸受体刺激诱发的海马神经元和星形胶质细胞释放APPs。鉴于已知皮质和海马中的谷氨酸能神经元在阿尔茨海默病中受损，我们的研究结果表明，由此产生的谷氨酸缺乏可能会增强淀粉样蛋白的形成，并且选择性mGluR激动剂可能有助于促进突触效能并治疗该疾病。
