ALZHEIMER'S DISEASE Misled by Metabolites

Misfolded amyloid ß peptides (Aß), which act as seeds for aggregates of insoluble amyloid, have been associated with the pathophysiology of Alzheimer's disease (AD). However, it is not clear what might initiate the abnormal folding of proteins with normal amino acid sequences. Noting that both hypercholesterolemia and inflammation increase the risk of developing AD, and that ozone production during inflammation has recently been demonstrated, Zhang et al. investigated the possibility that cholesterol ozonolysis metabolites could stimulate Aß misfolding. The authors used thioflavin T fluorescence and atomic force microscopy to show that two such cholesterol metabolites promoted aggregation of Aß peptides in vitro. Further, the resulting aggregates acted as seeds for amyloid fibrils. Both metabolites covalently bound Aß and lowered the concentration of Aß at which aggregates formed. Moreover, analysis by high-performance liquid chromatography-mass spectrometry revealed that both metabolites were present in human brain. These observations suggest a plausible scenario in which cholesterol-metabolite promotion of amyloidogenesis could underlie the association of both inflammation and hypercholesterolemia with AD.

Q. Zhang, E. T. Powers, J. Nieva, M. E. Huff, M. A. Dendle, J. Bieshchke, C. G. Glabe, A. Eschenmoser, P. Wentworth, Jr., R. A. Lerner, J. W. Kelly, Metabolite-initiated protein misfolding may trigger Alzheimer's disease. Proc. Natl. Acad. Sci. U.S.A. 101, 4752-4757 (2004). [Abstract] [Full Text]