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 Aβ 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 Aβ 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-Aβ 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.