Differential activation of neuronal ERK, JNK/SAPK and p38 in Alzheimer disease: the ‘two hit’ hypothesis

• Published in: Mechanisms of ageing and development 2001-12, Vol.123 (1), p.39-46
• Main Authors: Zhu, Xiongwei, Castellani, Rudolph J, Takeda, Atsushi, Nunomura, Akihiko, Atwood, Craig S, Perry, George, Smith, Mark A
• Format: Article
• Language: English
• Subjects: Adolescent; Adult; Aged; Aged, 80 and over; Alzheimer disease; Alzheimer Disease - enzymology; Alzheimer Disease - pathology; Biological and medical sciences; Cerebral Cortex - enzymology; Cerebral Cortex - pathology; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Enzyme Activation; Hippocampus - enzymology; Hippocampus - pathology; Humans; JNK Mitogen-Activated Protein Kinases; MAPK mitogen; Medical sciences; Middle Aged; Mitogen-Activated Protein Kinase 1 - metabolism; Mitogen-Activated Protein Kinase 3; Mitogen-Activated Protein Kinases - metabolism; Neurology; Neurons - enzymology; Oxidative stress; p38 Mitogen-Activated Protein Kinases; Phosphorylation
• ISSN: 0047-6374; 1872-6216
• 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.