Alzheimer's disease is characterized by the self-assembly of tau and amyloid β proteins into oligomers and fibrils. Tau protein assembles into paired helical filaments (PHFs) that constitute the neurofibrillary tangles observed in neuronal cell bodies in individuals with Alzheimer's disease. The mechanism of initiation of tau assembly into PHFs is not well understood. Here we report that a truncated 95-amino-acid tau fragment (corresponding to residues 297-391 of full-length tau) assembles into PHF-like fibrils in vitro without the need for other additives to initiate or template the process. Using electron microscopy, circular dichroism and X-ray fiber diffraction, we have characterized the structure of the fibrils formed from truncated tau for the first time. To explore the contribution of disulfide formation to fibril formation, we have compared the assembly of tau(297-391) under reduced and non-reducing conditions and for truncated tau carrying a C322A substitution. We show that disulfide bond formation inhibits filament assembly and that the C322A variant rapidly forms long and highly ordered PHFs.

Background: Tau aggregation inhibitors could treat Alzheimer disease.Results: Stable reduced forms of leucomethylthioninium (LMTX®) are active in blocking prion-like Tau aggregation in novel cellular models.Conclusion: The intracellular Ki (0.12 μm) is comparable with brain levels required for clinical benefit.Significance: LMTX® could treat Alzheimer disease.

The room-temperature syntheses and single-crystal structures of C(4)N(2)H(12).NH(4)Cl(3).H(2)O and C(6)N(2)H(14).NH(4)Cl(3) are reported. These novel molecular perovskites contain vertex-sharing octahedral (NH(4))Cl(6) arrays which replicate the octahedral packing in the cubic (SrTiO(3)) and 2-H hexagonal (BaNiO(3)) perovskite structures, respectively. The structures are completed by doubly protonated organic cations and, for the cubic phase, water molecules. Crystal data: C(4)N(2)H(12).NH(4)Cl(3).H(2)O, M(r) = 230.56, orthorhombic, Pbcm (No. 57), a = 6.5279(13) A, b = 12.935(3) A, c = 12.849(3) A, V = 1085.0(4) A(3), Z = 4; C(6)N(2)H(14).NH(4)Cl(3), M(r) = 238.59, trigonal, Pthremacr;c1 (No. 165), a = 16.1616(2) A, c = 22.3496(4) A, V = 5055.5(2) A(3), Z = 18.

Solvent contains ethanol. In ['HJthf. ' v(Rh-H) 1884 cm I . ' In C6D6. ' v(Rh-H) 1880 cm I . In C2D,0D. ' In CD2C12. j Solvent contains CF,CH20H.

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