Implication of JNK pathway on tau pathology and cognitive decline in a senescence-accelerated mouse model

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• 作者：Lourdes Orejana ; Lucí ; a Barros-Miñ ; ones ; Norberto Aguirre¹ ; Elena Puerta ; ¹ ; ^{epuerta@alumni.unav.es}
• 关键词：AD ; Alzheimer's disease ; Cdk5 ; cyclin-dependent kinase ; GSK-3¦Â ; glycogen synthase kinase 3 beta ; JNK ; c-Jun N-terminal kinase ; MAPKs ; mitogen-activated protein kinases ; NFT ; neurofibrillary tangles ; PHF ; paired helical filaments ; PP2A ; protein phosphatas
• 刊名：Experimental Gerontology
• 出版年：2013
• 出版时间：June, 2013
• 年：2013
• 卷：48
• 期：6
• 页码：565-571
• 全文大小：562 K

文摘

The senescence accelerated mouse-prone 8 (SAMP8) strain of mice is an experimental model of accelerated senescence that also shares several pathological features with Alzheimer's disease. Among them, cognitive impairments and abnormal hyperphosphorylation of tau are ameliorated by the phosphodiesterase 5 inhibitor sildenafil, possibly through the modulation of Cdk5/p25 and Akt/GSK-3¦Â pathways. Here we studied the implication of protein phosphatase 2A (PP2A) and c-Jun N-terminal kinase (JNK) in the therapeutic effects of sildenafil. Results demonstrated that there were no differences in hippocampal PP2A protein levels or activity (measured by its inactive isoform phopho-PP2A Y307) when we compared 6-month old SAMP8 mice and age-matched control, SAMR1 mice, treated with saline or sildenafil (7.5 mg/kg i.p. for 4 weeks). However, this same treatment of sildenafil, that had been shown to reverse the cognitive impairment and tau hyperphosphorylation in this animal model, also reversed the increased levels of activated JNK (p-JNK) found in the hippocampus of SAMP8 mice. Moreover, the administration of the JNK inhibitor, D-JNKI-1 (0.2 mg/kg i.p. for 3 weeks) also ameliorated the cognitive deficits shown by SAMP8 mice in the Morris water maze and decreased hippocampal levels of phospho-c-Jun(Ser73). When phosphorylated tau (AT8 epitope) was analyzed a significant reduction was observed in the hippocampus of D-JNKI-1 treated SAMP8 mice, providing a plausible explanation for the attenuation of cognitive decline shown by these animals. These findings suggest the involvement of the JNK pathway on tau pathology and cognitive deficits shown by 6-month old SAMP8 mice. They also point to the modulation of this kinase to be among the mechanisms responsible for the beneficial effects shown by sildenafil.