Effects of a tacrine-8-hydroxyquinoline hybrid (IQM-622) on A尾 accumulation and cell death: Involvement in hippocampal neuronal loss in Alzheimer's disease

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• 作者：Desiree Antequera^a ; ^b ; ¹ ; Marta Bolos^a ; ^b ; ¹ ; Carlos Spuch^a ; ^b ; ^c ; Consuelo Pascual^a ; ^b ; Isidro Ferrer^b ; ^d ; Marí ; a Isabel Fernandez-Bachiller^e ; Marí ; a Isabel Rodrí ; guez-Franco^e ; Eva Carro^a ; ^b ; ^{carroeva@h120.es}
• 关键词：Alzheimer's disease ; Acetylcholinesterase inhibitors ; A尾 degradation ; Domoic acid ; Neuroprotection ; Transgenic mice
• 刊名：Neurobiology of Disease
• 出版年：2012
• 期刊代码：80_09699961
• 类别：neu
• 出版时间：June, 2012
• 卷：46
• 期：3
• 页码：682-691
• 文件大小：1670 K

摘要

Several studies have implicated the enzyme acetylcholinesterase (AChE) as well as several biometals in the pathogenesis of Alzheimer's disease (AD). A multifunctional molecule, the hybrid tacrine-8-hydroxyquinoline (named IQM-622), displays cholinergic, antioxidant, copper-complexing and neuroprotective properties. Using in vitro and in vivo models, we investigated the modulating effects of IQM-622 on amyloid 尾-protein (A尾)-induced pathology as well as on chemically induced neurodegeneration by domoic acid. In the first experimental model, we observed a significant decrease in brain A尾 deposits in IQM-622-treated APP/Ps1 mice for four weeks. Moreover, IQM-622 promoted the degradation of intracellular A尾 in astrocytes, and protected against A尾 toxicity in cultured astrocytes and neurons. These findings suggest that the neuroprotective effect of IQM-622 is not only related to AChE inhibition, but also involves other mechanisms, including the modulation of A尾-degradation pathways in AD brain. In this study we also compare the neuronal loss in CA1 hippocampal field of AD patients and of mice treated with domoic acid, giving similar patterns. Thus, we used a second experimental model by killing hippocampal neurons by domoic acid damage, in which IQM-622 increased survival in the CA1 and dentate gyrus regions of the hippocampus. Our observations suggest that administration of IQM-622 may have significant beneficial effects in neurodegenerative diseases, including AD, which course with acute or progressive neuronal death.