Amyloid-beta neurotoxicity is mediated by FISH adapter protein and ADAM12 metalloprotease activity.
Based on a variety of genetic, biochemical, and neuropathological evidence, amyloid-beta peptide (Abeta) has been suggested to be causal in Alzheimer's disease (AD). Abeta has been shown to mediate neurodegenerative and inflammatory changes associated with amyloid plaques, as well as exert direct neurotoxicity through oligomeric forms of Abeta. The mechanism of Abeta toxicity, however, remains largely unknown. In this work, we show that an early event after exposure of postmitotic neurons to Abeta 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 Abeta. Expression of an ADAM12 protease-deficient mutant (ADAM12DeltaMP) blocks Abeta-induced neuronal death, and expression of an N-terminal fragment of FISH reduces Abeta 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 ADAM12DeltaMP. Abeta 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 Abeta toxicity is mediated by FISH and ADAM12 and may provide insights into therapeutic strategies for AD treatment.
Malinin
Nikolay L
NL
Elan Pharmaceuticals, 1000 Gateway Boulevard, South San Francisco, CA 94080, USA.
Wright
Sarah
S
Seubert
Peter
P
Schenk
Dale
D
Griswold-Prenner
Irene
I
D051722:ADAM Proteins; D000072199:ADAM12 Protein; D033942:Adaptor Proteins, Vesicular Transport / Q000502:physiology*; D000544:Alzheimer Disease / Q000378:metabolism / Q000628:therapy; D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000818:Animals; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000378:metabolism; D006801:Humans; D008565:Membrane Proteins / Q000032:analysis / Q000502:physiology*; D008666:Metalloendopeptidases / Q000032:analysis / Q000502:physiology*; D009474:Neurons / Q000187:drug effects* / Q000473:pathology; D010766:Phosphorylation; D011817:Rabbits
D033942:Adaptor Proteins, Vesicular Transport; D016229:Amyloid beta-Peptides; D008565:Membrane Proteins; C478582:SH3PXD2A protein, human; D051722:ADAM Proteins; D000072199:ADAM12 Protein; C000606480:ADAM12 protein, human; D008666:Metalloendopeptidases