Premium
P2‐481: A high throughput screen identifies compounds that inhibit Alzheimer's peptide aggregation and reduce toxicity in vitro and in drosophila melanogaster
Author(s) -
McKoy Angela,
Hecht Michael
Publication year - 2011
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2011.05.1352
Subject(s) - thioflavin , in vivo , toxicity , in vitro , drosophila melanogaster , small molecule , peptide , amyloid (mycology) , protein aggregation , chemistry , high throughput screening , fibril , biochemistry , microbiology and biotechnology , biophysics , pharmacology , alzheimer's disease , biology , disease , medicine , genetics , inorganic chemistry , organic chemistry , pathology , gene
by A in both Aß40 and Aß42. We used a combination of biophysical and biochemical methods to study the assembly kinetics, fibril morphology, and initial oligomer size distribution of each analogue. The assembly information was correlated with measurement of Aß-induced cell death using the lactate dehydrogenase (LDH) release assay. Results: Consistent with our hypothesis, our toxicity experiments showed that the K16 A substitution caused complete loss of toxicity in Aß40 and >75% decrease in Aß42 toxicity arguing for a direct role of K16 in mediating Aß interaction with cellular membranes. Compared to the K16 A substitution, the effect of the K28 A was larger on the assembly and smaller on toxicity of both Aß40 and Aß42, supporting the hypothesis that the main role of K28 is in Aß folding and assembly. We found also that substitution of either K16 or K28 by A had a stronger effect on the assembly of Aß42 than on Aß40. Conclusions: Our study reveals key role for K16 in Aß toxicity and highlights the difference in assembly between Aß40 and Aß42. The data also underscore the importance of the amphipathic K side chain in Aß assembly and toxicity suggesting that K16 and K28 may be targets for design and development of inhibitors of Aß aggregation and toxicity.