Tau Paired Helical Filaments from Alzheimer's Disease Brain and Assembled in Vitro Are Based on β-Structure in the Core Domain

Abstract

Tau protein, a neuronal microtubule-associated protein, forms insoluble fibers ("paired helical filaments") in Alzheimer's disease and other tauopathies. Conflicting views on the structure of the fibers have been proposed recently, ranging from mainly R-helical structure to mainly -sheet, or a mixture of mostly random coil and -sheet. We have addressed this issue by studying tau fibers immunopurified from Alzheimer brain tissue by a conformation-specific antibody and comparing them with fibers reassembled from recombinant tau or tau constructs in vitro, using a combination of electron microscopy and spectroscopic methods. Brain-derived fibers and reassembled fibers both exhibit a typical twisted appearance when examined by electron microscopy. The soluble tau protein is a natively unfolded protein dominated by random coil structure, whereas Alzheimer PHFs and reassembled fibers show a shift toward an increase in the level of -structure. The results support a model in which the repeat domain of tau (which lies within the core of PHFs) adopts an increasing level of -structure during aggregation, whereas the N-and C-terminal domains projecting away from the PHF core are mostly random coil.

Characterization of Prefibrillar Tau Oligomers in Vitro and in Alzheimer Disease

“…As an additional control, we also tested a construct that possessed only the MTBRs (Gln 244 -Glu 372 ), and TOC1 showed no affinity for this construct. This indicates that this antibody does not recognize the portion of the Tau aggregates possessing ␤-pleated sheets (57) in the absence of the rest of the Tau molecule. Nonetheless, we cannot entirely rule out the possibility that the MTBRs comprise part of the epitope.…”

Biochemistry and Cell Biology of Tau Protein in Neurofibrillary Degeneration

“…The small size of the b-motifs, embedded in a disordered protein, made it difficult to detect their role, so that the nature of Tau as an "amyloid" protein remained controversial for a long time. However, the b-structure has now been verified by circular dichroism and FTIR (Barghorn et al 2004), NMR (Mukrasch et al 2009), electron diffraction (Berriman et al 2003), X-ray fiber diffraction (Giannetti et al 2000), and even X-ray crystallography (Sawaya et al 2007). While the presence of a cross-b structure in the core of PHFs is unambiguous, its arrangement in detail is still unknown.…”

Nanoscopic Characterisation of Individual Endogenous Protein Aggregates in Human Neuronal Cells

“…In AD, the protein tau is deposited in intracellular inclusions,2 while the amyloid beta (Aβ) peptide is in extracellular plaques. Similarly, in PD, aggregates of the protein α‐synuclein (αS) are found in Lewy bodies3 within neuronal cells.…”