De Ferrari G V, Chacón M A, Barría M I, Garrido J L, Godoy J A, Olivares G, Reyes A E, Alvarez A, Bronfman M, Inestrosa N C
Centro de Regulación Celular y Patología, MIFAB, Facultad de Ciencias Biológicas, P Universidad Católica de Chile, Santiago, Chile.
Mol Psychiatry. 2003 Feb;8(2):195-208. doi: 10.1038/sj.mp.4001208.
Alzheimer's disease (AD) is a progressive neurodegenerative disorder, which is probably caused by the cytotoxic effect of the amyloid beta-peptide (Abeta). We report here molecular changes induced by Abeta, both in neuronal cells in culture and in rats injected in the dorsal hippocampus with preformed Abeta fibrils, as an in vivo model of the disease. Results indicate that in both systems, Abeta neurotoxicity resulted in the destabilization of endogenous levels of beta-catenin, a key transducer of the Wnt signaling pathway. Lithium chloride, which mimics Wnt signaling by inhibiting glycogen synthase kinase-3beta promoted the survival of post-mitotic neurons against Abeta neurotoxicity and recovered cytosolic beta-catenin to control levels. Moreover, the neurotoxic effect of Abeta fibrils was also modulated with protein kinase C agonists/inhibitors and reversed with conditioned medium containing the Wnt-3a ligand. We also examined the spatial memory performance of rats injected with preformed Abeta fibrils in the Morris water maze paradigm, and found that chronic lithium treatment protected neurodegeneration by rescuing beta-catenin levels and improved the deficit in spatial learning induced by Abeta. Our results are consistent with the idea that Abeta-dependent neurotoxicity induces a loss of function of Wnt signaling components and indicate that lithium or compounds that mimic this signaling cascade may be putative candidates for therapeutic intervention in Alzheimer's patients.
阿尔茨海默病（AD）是一种进行性神经退行性疾病，可能由β-淀粉样肽（Aβ）的细胞毒性作用引起。我们在此报告Aβ诱导的分子变化，这些变化既发生在培养的神经元细胞中，也发生在作为该疾病体内模型的、向背侧海马注射预形成Aβ纤维的大鼠中。结果表明，在这两种系统中，Aβ神经毒性导致Wnt信号通路的关键转导分子β-连环蛋白内源性水平的不稳定。氯化锂通过抑制糖原合酶激酶-3β模拟Wnt信号，促进有丝分裂后神经元抵抗Aβ神经毒性的存活，并使胞质β-连环蛋白恢复到对照水平。此外，Aβ纤维的神经毒性作用也受到蛋白激酶C激动剂/抑制剂的调节，并用含有Wnt-3a配体的条件培养基逆转。我们还在莫里斯水迷宫范式中检测了向背侧海马注射预形成Aβ纤维的大鼠的空间记忆表现，发现慢性锂治疗通过挽救β-连环蛋白水平保护神经退行性变，并改善由Aβ诱导的空间学习缺陷。我们的结果与以下观点一致，即Aβ依赖性神经毒性诱导Wnt信号成分功能丧失，并表明锂或模拟该信号级联的化合物可能是阿尔茨海默病患者治疗干预的潜在候选物。
