NR AQRQ
AU Pappolla,M.A.; Soto,C.; Bozner,P.; Frangione,B.; Ghiso,J.
TI Melatonin prevents formation of ß-sheets and fibrils of ß-amyloid. A new therapy for AD?
QU Journal of Neuropathology and Experimental Neurology 1996; 55(N5): 575 Nr. 15
VT It is generally postulated that the progressive neurodegeneration observed in sporadic A1zheimer's disease (AD) is a consequence, at least in part, of the neurotoxic properties of the ß-amyloid protein (Aß). Previous studies have shown an association between aggregation and the secondary structure of Aß, and its ability to promote neurodegeneration. In addition, these mentioned characteristics of Aß appear to determine its increased resistance to proteolysis and impaired clearance (key elements for ainyloid accumulation). We report that melatonin, a pineal hormone recently found to protect cells against Aß toxicity (Pappolla et al. J Neurosci, in press), markedly inhibited the progressive formation of ß-sheet structures in Aß, as well as its polymerisation into fibrils. We have used circular dichroism (CD) and electron microscopy to monitor the gradual development of ß-sheets and of fibrillogenesis, respectively, of solutions containing Aß(l-40). As expected, the content in ß-sheet conformation of the Aß(l-40) peptide incubated alone increased with time, reaching a maximum value after 24 hr at 37 C. This structure (76% ß-sheet and 16% random coil) strikingly changed by the addition of melatonin to sister tubes. In this case, there was an increase of the random conformation (67%) while the original values of ß-sheet dramatically diminished, reaching 30.7% after 24 hr incubation under identical conditions. Ultrastructural examination (2 day incubation) paralleled the conformational changes with virtually no fibrils detected in the tubes containing melatonin at various molarity ratios above 1:25 (melatonin:Aß). In contrast, a profuse number of amyloid fibrils were easily detected in the absence of melatonin. Remarkably, these effects were not observed in control preparations containing the melatonin analog 5-hydroxy-N-acetyl-tryptamine. These findings suggest a novel therapeutic approach for AD.
IN Das von der Hypophyse sezernierte Hormon Melatonin löste in vitro Alzheimer-Amyloide auf und reduzierte binnen 24 Stunden den Anteil der ß-Faltblatt-Sekundärstrukturen des Aß-Alzheimermonomers von 76 auf 30,7%, wenn es in einem molaren Verhältnis von 1:25 dem Aß-Protein gegenüber stand.
AD M.A.Pappolla1*, C.Soto1, P.Bozner1, B.Frangione2, J. Ghiso2. 1-University of Soutli Alabama, Mobile; 2-New York University, New York.
PO USA
SP englisch
OR Prion-Krankheiten 6