Amyloid beta protein toxicity mediated by the formation of amyloid-beta protein precursor complexes.
The amyloid-beta protein precursor, a type 1 transmembrane protein, gives rise to the amyloid beta-protein, a neurotoxic peptide postulated to be involved in the pathogenesis of Alzheimer's disease. Here, we show that soluble amyloid beta 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 beta protein correlated with caspase-cleaved fragments of the amyloid precursor protein in brains of Alzheimer's disease subjects. These findings suggest that soluble amyloid beta protein-induced multimerization of the amyloid precursor protein may be another mechanism by which amyloid beta protein contributes to synapse loss and neuronal cell death seen in Alzheimer's disease.
Lu
Daniel C
DC
Department of Neurosciences, University of California-San Diego, 9500 Gilman Drive, Mail Code 0691, La Jolla, CA 92093-0691, USA.
Shaked
Gideon M
GM
Masliah
Eliezer
E
Bredesen
Dale E
DE
Koo
Edward H
EH
D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism / Q000633:toxicity; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism* / Q000633:toxicity*; D000818:Animals; D001921:Brain / Q000201:enzymology / Q000473:pathology; D020169:Caspases / Q000378:metabolism; D016923:Cell Death / Q000235:genetics; D045744:Cell Line, Tumor; D006801:Humans; D051379:Mice
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D020169:Caspases