Neurotoxicity of human amylin in rat primary hippocampal cultures: similarity to Alzheimer's disease amyloid-beta neurotoxicity.
Amylin, a 37-amino-acid amyloidogenic peptide, bears biophysical similarities to the amyloid-beta peptide (A beta) deposited in Alzheimer's disease. Using embryonic rat hippocampal cultures we tested whether amylin induces neurotoxicity similar to that previously observed with A beta(1-40). Treatment with human amylin(1-37) resulted in prominent toxicity as assessed by phase-contrast microscopy and quantification of lactate dehydrogenase in the medium. Amylin-induced neurotoxicity was morphologically similar to that induced by A beta(1-40). In contrast, the nonamyloidogenic rat amylin showed negligible neurotoxicity despite having 95% sequence similarity to human amylin. Only full-length human amylin was toxic; various amylin peptide fragments including amino acid residues 20-29 were nontoxic at similar concentrations. These studies suggest that unrelated amyloidogenic peptides like human amylin and A beta can adopt a similar neurotoxic conformation in vitro. Similar conformation-dependent neurotoxicity may drive the prominent neurite degeneration around compacted but not diffuse deposits of A beta in Alzheimer's disease.
May
P C
PC
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285.
Boggs
L N
LN
Fuson
K S
KS
D000595:Amino Acid Sequence; D000682:Amyloid / Q000633:toxicity*; D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000704:Analysis of Variance; D000818:Animals; D002478:Cells, Cultured; D006624:Hippocampus / Q000187:drug effects*; D006801:Humans; D058228:Islet Amyloid Polypeptide; D007770:L-Lactate Dehydrogenase / Q000032:analysis; D008969:Molecular Sequence Data; D009410:Nerve Degeneration / Q000187:drug effects*; D009474:Neurons / Q000166:cytology / Q000187:drug effects*; D009498:Neurotoxins / Q000633:toxicity*; D051381:Rats; D017386:Sequence Homology, Amino Acid
D000682:Amyloid; D016229:Amyloid beta-Peptides; D058228:Islet Amyloid Polypeptide; D009498:Neurotoxins; D007770:L-Lactate Dehydrogenase