Zhu X, Castellani R J, Takeda A, Nunomura A, Atwood C S, Perry G, Smith M A
Institute of Pathology, Case Western Reserve University, 2085 Adelbert Road, Cleveland, OH 44106, USA.
Mech Ageing Dev. 2001 Dec;123(1):39-46. doi: 10.1016/s0047-6374(01)00342-6.
There are multiple lines of evidence showing that oxidative stress and aberrant mitogenic signaling play an important role in the pathogenesis of Alzheimer disease. However, the chronological relationship between these and other events associated with disease pathogenesis is not known. Given the important role that mitogen-activated protein kinase (MAPK) pathways play in both mitogenic signaling (ERK) and cellular stress signaling (JNK/SAPK and p38), we investigated the chronological and spatial relationship between activated ERK, JNK/SAPK and p38 during disease progression. While all three kinases are activated in the same susceptible neurons in mild and severe cases (Braak stages III-VI), in non-demented cases with limited pathology (Braak stages I and II), both ERK and JNK/SAPK are activated but p38 is not. However, in non-demented cases lacking any sign of pathology (Braak stage 0), either ERK alone or JNK/SAPK alone can be activated. Taken together, these findings indicate that MAPK pathways are differentially activated during the course of Alzheimer disease and, by inference, suggest that both oxidative stress and abnormalities in mitotic signaling can independently serve to initiate, but both are necessary to propagate, disease pathogenesis. Therefore, we propose that both 'hits', oxidative stress and mitotic alterations, are necessary for the progression of Alzheimer disease.
有多条证据表明氧化应激和异常的促有丝分裂信号传导在阿尔茨海默病的发病机制中起重要作用。然而，这些因素与疾病发病机制相关的其他事件之间的时间顺序关系尚不清楚。鉴于丝裂原活化蛋白激酶（MAPK）通路在促有丝分裂信号传导（ERK）和细胞应激信号传导（JNK/SAPK和p38）中均发挥重要作用，我们研究了疾病进展过程中活化的ERK、JNK/SAPK和p38之间的时间和空间关系。在轻度和重度病例（Braak分期III-VI）中，所有这三种激酶在相同的易感神经元中被激活，而在病理改变有限的非痴呆病例（Braak分期I和II）中，ERK和JNK/SAPK均被激活，但p38未被激活。然而，在无任何病理迹象的非痴呆病例（Braak分期0）中，单独的ERK或单独的JNK/SAPK均可被激活。综上所述，这些发现表明MAPK通路在阿尔茨海默病病程中被差异性激活，由此推断，提示氧化应激和有丝分裂信号传导异常均可独立引发疾病发病机制，但两者都是疾病进展所必需的。因此，我们提出氧化应激和有丝分裂改变这两个“打击”对于阿尔茨海默病的进展都是必要的。
