Clusterin (apoJ) Alters the Aggregation of Amyloid β-Peptide (Aβ 1-42) and Forms Slowly Sedimenting Aβ Complexes That Cause Oxidative Stress

• Published in: Experimental neurology Vol. 136; no. 1; pp. 22 - 31
• Main Authors: Oda, Tomiichiro, Wals, Pat, Osterburg, Heinz H., Johnson, Steven A., Pasinetti, Giulio M., Morgan, Todd E., Rozovsky, Irina, Stine, W.Blaine, Snyder, Seth W., Holzman, Thomas F., Krafft, Grant A., Finch, Caleb E.
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Inc 01.11.1995; Elsevier
• Subjects: Alzheimer Disease - metabolism; Amyloid beta-Protein Precursor - metabolism; Animals; Biological and medical sciences; Clusterin; Complement Inactivator Proteins - metabolism; Complement Inactivator Proteins - pharmacology; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Dose-Response Relationship, Drug; Glycoproteins - immunology; Glycoproteins - metabolism; Glycoproteins - pharmacology; Humans; Immunohistochemistry; Medical sciences; Molecular Chaperones; Neurology; Oxidative Stress; PC12 Cells - metabolism; Radioligand Assay; Rats; Sucrose - pharmacology; Human; Atomic force microscopy; Oxidative stress; Nervous system diseases; Alzheimer disease; Pathogenesis; Apolipoproteins; In vitro; Sedimentation; Cerebral disorder; β Amyloid protein; Central nervous system disease; Serum; Degenerative disease; Molecular aggregation
• ISSN: 0014-4886; 1090-2430
• DOI: 10.1006/exnr.1995.1080

Clusterin (apoJ), a multifunctional apolipoprotein made by cells in the brain and many other locations, is associated with aggregated amyloid β-peptide (Aβ) in senile and diffuse plaques of Alzheimer's disease (AD). We observed that purified human serum clusterin partially blocked the aggregation of synthetic Aβ 1-42, as shown by centrifugal assays (14,000g × 10 min) and by atomic force (scanning probe) microscopy. Slowly sedimenting Aβ 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 Aβ, 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 Aβ may enhance the neurotoxicity of Aβ deposits in AD brains, because soluble complexes have a potential for diffusing to damage distal neurons.