Amyloid-β Neurotoxicity Is Mediated by FISH Adapter Protein and ADAM12 Metalloprotease Activity

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 102; no. 8; pp. 3058 - 3063
• Main Authors: Malinin, Nikolay L., Wright, Sarah, Seubert, Peter, Schenk, Dale, Griswold-Prenner, Irene, Iversen, L. L.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 22-02-2005; National Acad Sciences
• Subjects: ADAM Proteins; ADAM12 Protein; Adaptor Proteins, Vesicular Transport - physiology; Adenoviruses; Alzheimer Disease - metabolism; Alzheimer Disease - therapy; Alzheimer's disease; Amyloid beta-Peptides - toxicity; Animals; Antibodies; Biological Sciences; Cells, Cultured; Centrifugation; Cerebral Cortex - metabolism; Fish proteins; Humans; Immunoprecipitation; Membrane Proteins - analysis; Membrane Proteins - physiology; Metalloendopeptidases - analysis; Metalloendopeptidases - physiology; Neurology; Neurons; Neurons - drug effects; Neurons - pathology; Neuroscience; Neurotoxicity; Phosphorylation; Proteases; Proteins; Rabbits
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0408237102

Based on a variety of genetic, biochemical, and neuropathological evidence, amyloid-β peptide (Aβ) has been suggested to be causal in Alzheimer's disease (AD). Aβ has been shown to mediate neurodegenerative and inflammatory changes associated with amyloid plaques, as well as exert direct neurotoxicity through oligomeric forms of Aβ. The mechanism of Aβ toxicity, however, remains largely unknown. In this work, we show that an early event after exposure of postmitotic neurons to Aβ is tyrosine phosphorylation of FISH adapter protein. FISH binds to and potentially regulates certain ADAM family members. We present evidence that FISH and ADAM12 mediate the neurotoxic effect of Aβ. Expression of an ADAM12 protease-deficient mutant (ADAM12ΔMP) blocks Aβ-induced neuronal death, and expression of an N-terminal fragment of FISH reduces Aβ toxicity. The C-terminal fragment of FISH containing the ADAMs binding region is found to be sufficient for induction of neuronal death, which is prevented by coexpression of the ADAM12ΔMP. Aβ treatment, as well as expression of the C-terminal toxic FISH fragment, induces accumulation of ADAM12 N-terminal cleavage product in conditioned medium, demonstrating activation of the ADAM metalloprotease/sheddase activity. ADAM12 protein is reduced in AD brains, pointing to a possible increase in ADAM12 proteolytic activity. These data suggest that Aβ toxicity is mediated by FISH and ADAM12 and may provide insights into therapeutic strategies for AD treatment.