Humanin rescues human cerebrovascular smooth muscle cells from Abeta-induced toxicity.
Cerebral amyloid beta-protein (Abeta) angiopathy (CAA) is a key pathological feature of Alzheimer's disease (AD) and related disorders. We have used human cerebrovascular smooth muscle (HCSM) cells as an in vitro model system to investigate the pathogenic mechanisms of the pathology of CAA. It was previously demonstrated that certain pathogenic forms of Abeta induce several pathologic responses in these cells, including fibril assembly at the cell surface, increased levels of Abeta precursor, degradation of HCSM cell alpha-actin and cell death. The recently discovered novel rescue factor humanin (HN) was shown to protect neuronal cells in culture from various AD-relevant insults including treatment with Abeta. In this report we investigated whether the HN peptide could rescue HCSM cells from Abeta-induced toxicity. We found that treatment of HCSM cells with 10 microm HN prevented pathogenic Abeta-induced HCSM cell death using a fluorescent cell viability assay, and degradation of HCSM alpha-actin was diminished shown by quantitative immunoblotting. However, Abeta deposition and fibril formation at the cell surface and increased levels of cell-associated AbetaPP were not affected by treatment with HN as demonstrated by a thioflavin T fluorescence assay and immunochemical methods, respectively. These results suggest that the protective effects of HN occur downstream of these cell surface molecular events. This is the first demonstration of a rescue factor for HCSM cells from Abeta-mediated cell death as well as being the first report to show that neuronal cells and HCSM cells may share a common downstream mechanism in the Abeta-induced cell death pathway.
Jung
Sonia S
SS
Department of Medicine, Stony Brook University, New York 11794, USA.
Van Nostrand
William E
WE
D000199:Actins / Q000378:metabolism; D000328:Adult; D019943:Amino Acid Substitution; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000633:toxicity*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D002462:Cell Membrane / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002560:Cerebrovascular Circulation; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008578:Meninges / Q000098:blood supply; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D011506:Proteins / Q000235:genetics / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D000199:Actins; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D047908:Intracellular Signaling Peptides and Proteins; D011506:Proteins; C427211:humanin