Biochemical and Biophysical Research Communications, Vol.344, No.2, 471-477, 2006
Cytosolic amyloid-beta peptide 42 escaping from degradation induces cell death
Accumulating evidence suggests that intracellular amyloid-beta (A beta) peptide triggers the early pathological events in Alzheimer's disease (AD). However, little is known about the consequence of cytosolic A beta. In this study, we ectopically expressed A beta 42 in the cytoplasm of SH-SY5Y neuroblastoma cells by expressing a fusion protein of GFP-tagged ubiquitin and A beta 42 (GFPUb-A beta 42). Although GFPUb and A beta 42 are stochastically produced with the same molar ratio in the cytoplasm, A beta 42 was completely degraded in more than 50% of the GFPUb-expressing cells. However, if A beta 42 was not degraded in their cytoplasm, then A beta 42-expressing cells underwent apoptosis. The number of A beta 42-expressing cells is significantly increased by the inhibition of proteasome with MG132. Cytosolic A beta 42 which has escaped degradation inhibits proteasome and thereby may accelerate the accumulation of A beta 42 and its detrimental effects. Our findings suggest that cells have the potential to degrade A beta 42 in their cytoplasm but if A beta 42 appears in the cytoplasm due to its incomplete degradation, it accumulates and may trigger the fatal cascade of pathology of AD. (c) 2006 Elsevier Inc. All rights reserved.