Alpha2-macroglobulin attenuates beta-amyloid peptide 1-40 fibril formation and associated neurotoxicity of cultured fetal rat cortical neurons.
Beta-amyloid peptides (A beta) are deposited in an aggregated fibrillar form in both diffuse and senile plaques in the brains of patients with Alzheimer's disease. The neurotoxicity of A beta in cultured neurons is dependent on its aggregation state, but the factors contributing to aggregation and fibril formation are poorly understood. In the present study, we investigated whether alpha2-macroglobulin (alpha2M), a protein present in neuritic plaques and elevated in Alzheimer's disease brain, is a potential regulatory factor for A beta fibril formation. Previous studies in our laboratory have shown that alpha2M is an A beta binding protein. We now report that, in contrast to another plaque-associated protein, alpha1-antichymotrypsin, alpha2M coincubated with A beta significantly reduces aggregation and fibril formation in vitro. Additionally, cultured fetal rat cortical neurons are less vulnerable to the toxic actions of aged A beta following pretreatment with alpha2M. We postulate that alpha2M is able to maintain A beta in a soluble state, preventing fibril formation and associated neurotoxicity.
Du
Y
Y
Neuroscience Discovery Research, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285, USA.
Bales
K R
KR
Dodel
R C
RC
Liu
X
X
Glinn
M A
MA
Horn
J W
JW
Little
S P
SP
Paul
S M
SM
D000544:Alzheimer Disease / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology*; D004705:Endocytosis; D010450:Endopeptidases / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D009498:Neurotoxins / Q000494:pharmacology; D010446:Peptide Fragments / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology; D000514:alpha 1-Antichymotrypsin / Q000494:pharmacology; D000511:alpha-Macroglobulins / Q000494:pharmacology*
D016229:Amyloid beta-Peptides; D009498:Neurotoxins; D010446:Peptide Fragments; D015842:Serine Proteinase Inhibitors; D000514:alpha 1-Antichymotrypsin; D000511:alpha-Macroglobulins; C078592:amyloid beta-protein (1-40); D010450:Endopeptidases