Association of clusterin with the BRI2-derived amyloid molecules ABri and ADan

NEUROBIOLOGY OF DISEASE

卷:158

Article

Rostagno, Agueda¹  Calero, Miguel^2,3,4  Holton, Janice L.⁵  Revesz, Tamas^5,6  Lashley, Tammaryn^5,6  Ghiso, Jorge^1,7 

[1] NYU, Sch Med, Dept Pathol, New York, NY 10016 USA

[2] Inst Salud Carlos III, Madrid 28029, Spain

[3] Network Ctr Biomed Res Neurodegenerat Dis CIBERNE, Madrid 28031, Spain

[4] CIEN Fdn, Alzheimers Ctr Reina Sofia Fdn, Madrid 28031, Spain

[5] UCL Queen Sq Inst Neurol, Dept Clin & Movement Neurosci, Queen Sq Brain Bank Neurol Disorders, London WC1N 3BG, England

[6] UCL Queen Sq Inst Neurol, Dept Neurodegenerat Dis, London WC1N 3BG, England

[7] NYU, Sch Med, Dept Psychiat, New York, NY 10016 USA

关键词: Amyloid;    Alzheimer's disease;    Apo J;    Apolipoprotein J;    Chromosome 13 dementias;    Familial British dementia;    Familial Danish dementia;   

DOI  :  10.1016/j.nbd.2021.105452

来源: Elsevier

【 摘 要 】

Familial British and Danish dementias (FBD and FDD) share striking neuropathological similarities with Alzheimer's disease (AD), including intraneuronal neurofibrillary tangles as well as parenchymal and vascular amyloid deposits. Multiple amyloid associated proteins with still controversial role in amyloidogenesis colocalize with the structurally different amyloid peptides ABri in FBD, ADan in FDD, and A beta in AD. Genetic variants and plasma levels of one of these associated proteins, clusterin, have been identified as risk factors for AD. Clusterin is known to bind soluble A beta in biological fluids, facilitate its brain clearance, and prevent its aggregation. The current work identifies clusterin as the major ABri- and ADan-binding protein and provides insight into the biochemical mechanisms leading to the association of clusterin with ABri and ADan deposits. Mirroring findings in AD, the studies corroborate clusterin co-localization with cerebral parenchymal and vascular amyloid deposits in both disorders. Ligand affinity chromatography with downstream Western blot and amino acid sequence analyses unequivocally identified clusterin as the major ABri- and ADan-binding plasma protein. ELISA highlighted a specific saturable binding of clusterin to ABri and ADan with low nanomolar Kd values within the same range as those previously demonstrated for the clusterin-A beta interaction. Consistent with its chaperone activity, thioflavin T binding assays clearly showed a modulatory effect of clusterin on ABri and ADan aggregation/ fibrillization properties. Our findings, together with the known multifunctional activity of clusterin and its modulatory activity on the complex cellular pathways leading to oxidative stress, mitochondrial dysfunction, and the induction of cell death mechanisms - all known pathogenic features of these protein folding disorders - suggests the likelihood of a more complex role and a translational potential for the apolipoprotein in the amelioration/prevention of these pathogenic mechanisms.