Conformation-dependent tau antibodies, Alzheimer's disease, and related disorders

Abstract

The neurofibrillary degeneration seen in Alzheimer's disease (AD) develops when abnormally modified tau aggregates into paired helical filaments (PHF-tau). In-depth characterization of the these modifications intensified with the generation of Alz-50, an apparent conformation-dependent antibody that reacts with PHF. Alz-50 allowed the purification of PHF, which then was used to generate several generations of apparent conformation-dependent antibodies, including MC1 and TG3. Research goals included confirmation of the structural changes detected by Alz-50, MC1, and TG3.;While data supports, but is inconclusive regarding the exact nature of the structural requirements for Alz-50/MC1 reactivity with PHF-tau, TG3 has now been shown to recognize a disease-specific conformational change in tau. Additional panels of antibodies recognizing the same conformationally altered epitope have helped to confirm the immunodominant profile of this region of tau. This sequence, which includes a phosphorylation at amino acid 231, contains two beta-turns, the second of which relieves the steric hindrance of a phosphorylation at amino acid 235. Though this data identifies a truly disease-specific alteration of tau in AD, it was not known whether or not conformational change could contribute to neuronal cell death. Recently, the identification of tau mutations in Frontotemporal Dementia with Parkinsonism-17 has provided some insight on this matter. Single missense mutations in this disease cause conformational changes in tau that result in severe spongiosis, massive amounts of cell death, and the aggregation of tau into filamentous inclusions. Together, these data allow the generation of workable hypotheses on the role of structural alterations in PHF formation and subsequent neurofibrillary pathology.;The data presented in this thesis demonstrate that structural changes in tau contribute to neuronal degeneration. Discussions focus on the conformational hypothesis of AD, and the diagnostic capability of conformation-dependent antibodies to detect disease-specific alterations in AD.