Solas Maite, Vela Silvia, Smerdou Cristian, Martisova Eva, Martínez-Valbuena Iván, Luquin María-Rosario, Ramírez María J
Department of Pharmacology and Toxicology, University of Navarra, 31008 Pamplona, Spain.
IdISNA, Navarra Institute for Health Research, 31008 Pamplona, Spain.
ACS Chem Neurosci. 2023 Mar 28;14(8):1524-34. doi: 10.1021/acschemneuro.3c00093.
c-Jun N-terminal kinase 3 (JNK3) is suggested to play a key role in neurodegenerative disorders, especially in Alzheimer's disease (AD). However, it remains unclear whether JNK or amyloid β (Aβ) appears first in the disease onset. Postmortem brain tissues from four dementia subtypes of patients (frontotemporal dementia, Lewy body dementia, vascular dementia, and AD) were used to measure activated JNK (pJNK) and Aβ levels. pJNK expression is significantly increased in AD; however, similar pJNK expression was found in other dementias. Furthermore, there was a significant correlation, co-localization, and direct interaction between pJNK expression and Aβ levels in AD. Significant increased levels of pJNK were also found in Tg2576 mice, a model of AD. In this line, Aβ intracerebroventricular injection in wild-type mice was able to induce a significant elevation of pJNK levels. JNK3 overexpression, achieved by intrahippocampal injection of an adeno-associated viral vector expressing this protein, was enough to induce cognitive deficiencies and precipitate Tau aberrant misfolding in Tg2576 mice without accelerating amyloid pathology. JNK3 overexpression may therefore be triggered by increased Aβ. The latter, together with subsequent involvement of Tau pathology, may be underlying cognitive alterations in early stages of AD.
c-Jun氨基末端激酶3（JNK3）被认为在神经退行性疾病中起关键作用，尤其是在阿尔茨海默病（AD）中。然而，尚不清楚JNK或淀粉样β蛋白（Aβ）在疾病发作时哪个先出现。使用来自四种痴呆亚型患者（额颞叶痴呆、路易体痴呆、血管性痴呆和AD）的死后脑组织来测量活化的JNK（pJNK）和Aβ水平。pJNK表达在AD中显著增加；然而，在其他痴呆中也发现了类似的pJNK表达。此外，在AD中，pJNK表达与Aβ水平之间存在显著的相关性、共定位和直接相互作用。在AD模型Tg2576小鼠中也发现pJNK水平显著升高。在这方面，向野生型小鼠脑室内注射Aβ能够诱导pJNK水平显著升高。通过海马内注射表达该蛋白的腺相关病毒载体实现JNK3过表达，足以在Tg2576小鼠中诱导认知缺陷并促使Tau异常错误折叠，而不会加速淀粉样病变。因此，JNK3过表达可能由Aβ增加引发。后者与随后Tau病理的参与一起，可能是AD早期认知改变的基础。
