Premium
S2‐03–01: Tau‐associated neurodegeneration in Alzheimer's Disease and tauopathy
Author(s) -
Spillantini Maria Grazia
Publication year - 2008
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2008.05.283
Subject(s) - neurodegeneration , tauopathy , tau protein , frontotemporal dementia , progressive supranuclear palsy , biology , gene isoform , microbiology and biotechnology , microtubule , binding domain , neuroscience , genetics , gene , alzheimer's disease , dementia , medicine , binding site , disease , pathology , atrophy
important pathological features, such as accumulation of misfolded proteins as amyloid oligomers and fibrils and dysregulation of cellular function. Recent evidence suggests that soluble amyloid oligomers may represent the primary pathological species of protein aggregates and not the mature amyloid fibrils. Methods: We have produced two specific conformation-dependent antisera and a number of monoclonal antibodies that recognize mutually exclusive, generic epitopes associated with prefibrillar oligomers and amyloid fibrils. Results: These antibodies specifically recognize these assembly states from many different types of amyloids, indicating that the assembly states share a generic structural motif that may mediate toxicity by common mechanisms. Analysis of synthetic A oligomers by western blotting indicates that the antisera specifically and mutually exclusively stain homogeneous preparations of prefibrillar oligomers and fibrils, but the sizes of bands recognized by the different antibodies are broadly overlapping. These results indicate that size is not a reliable indicator of oligomer conformation. Both antisera detect naturally occurring amyloid oligomers in human AD brain, but the soluble fibrillar oligomers correlate best with disease. Monoclonal antibodies specific for prefibrillar oligomers indicate that structural polymorphisms exist in A prefibrillar oligomers that vary in their reactivity with monoclonal antibodies. Conclusions: These results suggest that distinct structural variants of soluble A oligomers exist, analogous to different strains of prions. Conformation dependent monoclonal antibodies are facile tools for distinguishing different types of soluble oligomers, both in vitro and in vivo and for elucidating the structure of amyloid oligomer variants.