Amyloid β protein toxicity mediated by the formation of amyloid-β protein precursor complexes

• Published in: Annals of neurology Vol. 54; no. 6; pp. 781 - 789
• Main Authors: Lu, Daniel C., Shaked, Gideon M., Masliah, Eliezer, Bredesen, Dale E., Koo, Edward H.
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 01.12.2003; Willey-Liss
• Subjects: Amyloid beta-Peptides - genetics; Amyloid beta-Peptides - metabolism; Amyloid beta-Peptides - toxicity; Amyloid beta-Protein Precursor - genetics; Amyloid beta-Protein Precursor - metabolism; Amyloid beta-Protein Precursor - toxicity; Animals; Biological and medical sciences; Brain - enzymology; Brain - pathology; Caspases - metabolism; Cell Death - genetics; Cell Line, Tumor; Humans; Medical sciences; Mice; Neurology; Nervous system diseases; β Amyloid protein; Toxicity; Amyloid precursor protein
• ISSN: 0364-5134; 1531-8249
• DOI: 10.1002/ana.10761

The amyloid‐β protein precursor, a type 1 transmembrane protein, gives rise to the amyloid β‐protein, a neurotoxic peptide postulated to be involved in the pathogenesis of Alzheimer's disease. Here, we show that soluble amyloid β protein accelerates amyloid precursor protein complex formation, a process that contributes to neuronal cell death. The mechanism of cell death involves the recruitment of caspase‐8 to the complex, followed by intracytoplasmic caspase cleavage of amyloid precursor protein. In vivo, the levels of soluble amyloid β protein correlated with caspase‐cleaved fragments of the amyloid precursor protein in brains of Alzheimer's disease subjects. These findings suggest that soluble amyloid β protein–induced multimerization of the amyloid precursor protein may be another mechanism by which amyloid β protein contributes to synapse loss and neuronal cell death seen in Alzheimer's disease. Ann Neurol 2003;54:781–789