Clusterin (apoJ) alters the aggregation of amyloid beta-peptide (A beta 1-42) and forms slowly sedimenting A beta complexes that cause oxidative stress.
Clusterin (apoJ), a multifunctional apolipoprotein made by cells in the brain and many other locations, is associated with aggregated amyloid beta-peptide (A beta) in senile and diffuse plaques of Alzheimer's disease (AD). We observed that purified human serum clusterin partially blocked the aggregation of synthetic A beta 1-42, as shown by centrifugal assays (14,000g x 10 min) and by atomic force (scanning probe) microscopy. Slowly sedimenting A beta complexes were formed in the presence of clusterin, which included aggregates > 200 kDa that resist dissociation by low concentrations of SDS. Clusterin enhanced the oxidative stress caused by A beta, as assayed by oxidative stress in PC12 cells with MTT, which is widely used to estimate neurotoxicity. These indications of enhanced neurotoxicity by the MTT assay were observed in the highly aggregated rapidly sedimenting fraction, but also in more slowly sedimenting "soluble" forms. This novel activity of slowly sedimenting A beta may enhance the neurotoxicity of A beta deposits in AD brains, because soluble complexes have a potential for diffusing to damage distal neurons.
Oda
T
T
Neurogerontology Division, Andrus Gerontology Center, University of Southern California, Los Angeles 90089-0191, USA.
Wals
P
P
Osterburg
H H
HH
Johnson
S A
SA
Pasinetti
G M
GM
Morgan
T E
TE
Rozovsky
I
I
Stine
W B
WB
Snyder
S W
SW
Holzman
T F
TF
D000544:Alzheimer Disease / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D051152:Clusterin; D003169:Complement Inactivator Proteins / Q000378:metabolism / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006023:Glycoproteins / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D007150:Immunohistochemistry; D018832:Molecular Chaperones; D018384:Oxidative Stress; D016716:PC12 Cells / Q000378:metabolism; D011869:Radioligand Assay; D051381:Rats; D013395:Sucrose / Q000494:pharmacology
D016564:Amyloid beta-Protein Precursor; C495242:CLU protein, human; D051152:Clusterin; D003169:Complement Inactivator Proteins; D006023:Glycoproteins; D018832:Molecular Chaperones; D013395:Sucrose