Differential modification of Cys10 alters transthyretin's effect on beta-amyloid aggregation and toxicity.
Tg2576 mice produce high levels of beta-amyloid (Abeta) and develop amyloid deposits, but lack neurofibrillary tangles and do not suffer the extensive neuronal cell loss characteristic of Alzheimer's disease. Protection from Abeta toxicity has been attributed to up-regulation of transthyretin (TTR), a normal component of plasma and cerebrospinal fluid. We compared the effect of TTR purified from human plasma (pTTR) with that produced recombinantly (rTTR) on Abeta aggregation and toxicity. pTTR slowed Abeta aggregation but failed to protect primary cortical neurons from Abeta toxicity. In contrast, rTTR accelerated aggregation, while effectively protecting neurons. This inverse correlation between Abeta aggregation kinetics and toxicity is consistent with the hypothesis that soluble intermediates rather than insoluble fibrils are the most toxic Abeta species. We carried out a detailed comparison of pTTR with rTTR to ascertain the probable cause of these different effects. No differences in secondary, tertiary or quaternary structure were detected. However, pTTR differed from rTTR in the extent and nature of modification at Cys10. We hypothesize that differential modification at Cys10 regulates TTR's effect on Abeta aggregation and toxicity.
Liu
Lin
L
Department of Chemical and Biological Engineering, University of Wisconsin, 1415 Engineering Drive, Madison, WI 53706, USA.
Hou
Jie
J
Du
Jiali
J
Chumanov
Robert S
RS
Xu
Qingge
Q
Ge
Ying
Y
Johnson
Jeffrey A
JA
Murphy
Regina M
RM
D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D002470:Cell Survival; D002478:Cells, Cultured; D002942:Circular Dichroism; D003545:Cysteine / Q000378:metabolism*; D004591:Electrophoresis, Polyacrylamide Gel; D005260:Female; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D013058:Mass Spectrometry; D051379:Mice; D046529:Microscopy, Electron, Transmission; D009474:Neurons / Q000166:cytology / Q000187:drug effects; D011228:Prealbumin / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D055503:Protein Multimerization; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology
D016229:Amyloid beta-Peptides; D011228:Prealbumin; D011994:Recombinant Proteins; D003545:Cysteine