Clusterin Promotes Amyloid Plaque Formation and is Critical for Neuritic Toxicity in a Mouse Model of Alzheimer's Disease

• Published in: Proceedings of the National Academy of Sciences - PNAS 2002-08, Vol.99 (16), p.10843-10848
• Main Authors: DeMattos, Ronald B., O'dell, Mark A., Parsadanian, Maia, Taylor, Jennie W., Judith A. K. Harmony, Bales, Kelly R., Paul, Steven M., Aronow, Bruce J., Holtzman, David M.
• Format: Article
• Language: English
• Subjects: Alzheimer Disease - metabolism; Alzheimer Disease - pathology; Alzheimer's disease; Alzheimers disease; Amyloid beta-Peptides - metabolism; Amyloid beta-Protein Precursor - metabolism; Amyloid plaque; Amyloids; Animals; Antibodies; Biological Sciences; Biology; Brain; Brain - metabolism; Brain - pathology; Clusterin; Disease Models, Animal; Gels; Glycoproteins - genetics; Glycoproteins - physiology; Hippocampus; Mice; Mice, Knockout; Molecular Chaperones - genetics; Molecular Chaperones - physiology; Neurites; Neurites - metabolism; Neurites - pathology; Neurology; Neuroscience; Peptide Fragments - metabolism; Plaque, Amyloid - metabolism; Plaque, Amyloid - pathology; Rodents; Thiazoles - metabolism; Toxicity
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.162228299

Studies have shown that clusterin (also called apolipoprotein J) can influence the structure and toxicity of amyloid-β (Aβ) in vitro. To determine whether endogenous clusterin plays a role in influencing Aβ deposition, structure, and toxicity in vivo, we bred PDAPP mice, a transgenic mouse model of Alzheimer's disease, to clusterin-/-mice. By 12 months of age, PDAPP, clusterin-/-mice had similar levels of brain Aβ deposition as did PDAPP, clusterin+/+mice. Although Aβ deposition was similar, PDAPP, clusterin-/-mice had significantly fewer fibrillar Aβ (amyloid) deposits than PDAPP mice expressing clusterin. In the absence of clusterin, neuritic dystrophy associated with the deposited amyloid was markedly reduced, resulting in a dissociation between fibrillar amyloid formation and neuritic dystrophy. These findings demonstrate that clusterin markedly influences Aβ structure and neuritic toxicity in vivo and is likely to play an important role in Alzheimer's disease pathogenesis.