Annals of Neurology 2003 (Dec); 54 (6): 781–789
Daniel C. Lu MD, PhD Gideon M. Shaked PhD Eliezer Masliah MD Dale E. Bredesen MD Edward H. Koo MD
Department of Neurosciences,
University of California-San Diego,
9500 Gilman Drive,
Mail Code 0691, La Jolla, CA 92093-0691, USA.
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.