Molecular Mechanism of Apoptosis by Amyloid β-Protein Fibrils Formed on Neuronal Cells
Eri Takada, Kaori Okubo, Yoshiaki Yano, Keiko Iida, Masataka Someda, Akira Hirasawa, Shin Yonehara, Katsumi Matsuzaki
Abstract
Aggregational states of amyloid β-protein (Aβ) are critical for its neurotoxicity, although they are not well-characterized, particularly after binding to the cell membranes. This is one reason why the mechanisms of Aβ neurotoxicity are controversial and elusive. In this study, the effects of toxic Aβ-(1-42) fibrils formed in the membrane on cellular processes were investigated using human neuroblastoma SH-SY5Y cells. Consistent with previous observations, fibrillar Aβs formed on the membranes induced activation of caspase-3, the effector caspase for apoptosis. Knockdown analyses of the initiator caspases, caspase-8 and caspase-9, indicated that the apoptosis was induced via activation of caspase-8, followed by activation of caspase-9 and caspase-3. We also found that inflammation signaling pathways including Toll-like receptors and inflammasomes NOD-, LRR-, and pyrin domain-containing protein 3 are involved in the initiation of apoptosis by the Aβ fibrils. These inflammation-related molecules are promising targets for the prevention of apoptotic cell death induced by Aβ.