Ligand-Dependent Tau Filament Formation:  Implications for Alzheimer's Disease Progression

King, Michelle E.; Ahuja, Vibha; Binder, Lester I.; Kuret, Jeff

doi:10.1021/bi9911839

Cited by 142 publications

(217 citation statements)

References 47 publications

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“…Above their critical micelle concentrations (CMCs) 1 in aqueous solution, fatty acids form micelles in which their hydrophobic moieties are sequestered, and their charged head groups are exposed to solvent. We (6) and others (16) have argued that the behavior of fatty acids such as arachidonic acid in assays of tau aggregation was consistent with it acting in micellar form. Yet fatty acids induce tau fibrillization at concentrations well below their measured CMC values (14).…”

supporting

confidence: 62%

“…Fibrillization of recombinant, full-length tau protein in vitro does not occur spontaneously at physiological concentrations (6). However, tau protein can be induced to fibrillize by changes in its primary structure (7) or its state of posttranslational modification (8,9); by the addition of polyanionic substances such as sulfated glycosaminoglycans (heparin, dextran sulfate, and pentosan polysulfate) (10 -12), polyglutamate (11), and RNA (13); or by addition of fatty acids (14).…”

mentioning

confidence: 99%

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Anionic Micelles and Vesicles Induce Tau Fibrillization in Vitro

Chirita

Necula

Kuret

2003

Journal of Biological Chemistry

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220

255

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Alzheimer's disease is defined in part by the intraneuronal accumulation of filaments comprised of the microtubule-associated protein tau. In vitro, fibrillization of recombinant tau can be induced by treatment with various agents, including phosphotransferases, polyanionic compounds, and fatty acids. Here we characterize the structural features required for the fatty acid class of tau fibrillization inducer using recombinant fulllength tau protein, arachidonic acid, and a series of straight chain anionic, cationic, and nonionic detergents. Induction of measurable tau fibrillization required an alkyl chain length of at least 12 carbons and a negative charge consisting of carboxylate, sulfonate, or sulfate moieties. All detergents and fatty acids were micellar at active concentrations, due to a profound, taudependent depression of their critical micelle concentrations. Anionic surfaces larger than detergent micelles, such as those supplied by phosphatidylserine vesicles, also induced tau fibrillization with resultant filaments originating from their surface. These data suggest that anionic surfaces presented as micelles or vesicles can serve to nucleate tau fibrillization, that this mechanism underlies the activity of fatty acid inducers, and that anionic membranes may serve this function in vivo.

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supporting

confidence: 62%

mentioning

confidence: 99%

Anionic Micelles and Vesicles Induce Tau Fibrillization in Vitro

Chirita

Necula

Kuret

2003

Journal of Biological Chemistry

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220

255

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“…Binding to these surfaces may concentrate ␣-synuclein mole- cules such that the energy barrier for nucleation is overcome, as suggested for other aggregating proteins (39,47). Consistent with this hypothesis, ␣-synuclein filaments occasionally could be observed extending from the surface of vesicles composed of pure anionic lipid (Fig.…”

Section: Discussionmentioning

confidence: 90%

“…Electron Microscopy Assay-Aliquots of ␣-synuclein aggregation reactions (50 l) were removed, treated with 2% glutaraldehyde (final concentration), adsorbed onto Formvar/carbon-coated 300 mesh grids (1 min), and negatively stained with 2% uranyl acetate (1-2 min) as described previously (39). Images were viewed in a Phillips CM 12 transmission electron microscope operated at 65 kV.…”

Section: Materials-arachidonicmentioning

confidence: 99%

Rapid Anionic Micelle-mediated α-Synuclein Fibrillization in Vitro

Necula¹,

Chirita²,

Kuret

2003

Journal of Biological Chemistry

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Parkinson's disease is characterized by the aggregation of ␣-synuclein into filamentous forms within affected neurons of the basal ganglia. Fibrillization of purified recombinant ␣-synuclein is inefficient in vitro but can be enhanced by the addition of various agents including glycosaminoglycans and polycations. Here we report that fatty acids and structurally related anionic detergents greatly accelerate fibrillization of recombinant ␣-synuclein at low micromolar concentrations with lag times as short as 11 min and apparent first order growth rate constants as fast as 10.4 h ؊1 . All detergents and fatty acids were micellar at active concentrations because of an ␣-synuclein-dependent depression of their critical micelle concentrations. Other anionic surfaces, such as those supplied by anionic phospholipid vesicles, also induced ␣-synuclein fibrillization, with resultant filaments originating from their surface. These data suggest that anionic surfaces presented as micelles or vesicles can serve to nucleate ␣-synuclein fibrillization, that this mechanism underlies the inducer activity of anionic surfactants, and that anionic membranes may serve this function in vivo.

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“…However, aggregation can be dramatically accelerated by polyanionic cofactors such as sulfated glycosaminoglycans, RNA, acidic peptides, or fatty acid micelles (7)(8)(9)(10). The aggregation is thought to follow a nucleation-elongation pathway (11), whereby an oligomeric nucleus is first formed by self-association of protein subunits, followed by addition of subunits to filament ends.…”

mentioning

confidence: 99%

Stepwise proteolysis liberates tau fragments that nucleate the Alzheimer-like aggregation of full-length tau in a neuronal cell model

Wang

Biernat

Pickhardt

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

176

178

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Tau is a highly soluble protein, yet it aggregates abnormally in Alzheimer's disease. Here, we address the question of proteolytic processing of tau and the nucleation of aggregates by tau fragments. We show in neuronal cell models that fragments of the repeat domain of tau containing mutations of FTDP17 (frontotemporal dementia with parkinsonism linked to chromosome 17), produced by endogenous proteases, can induce the aggregation of full-length tau. Fragments are generated by successive cleavages, first N-terminally between K257 and S258, then C-terminally around residues 353-364; conversely, when the N-terminal cleavage is inhibited, no fragmentation and aggregation takes place. The C-terminal truncation and the coaggregation of fragments with full-length tau depends on the propensity for ␤-structure. The aggregation is modulated by phosphorylation but does not depend on it. Aggregation but not fragmentation as such is toxic to cells; conversely, toxicity can be prevented by inhibiting either aggregation or proteolysis. The results reveal a novel pathway of abnormal tau aggregation in neuronal cells.Alzheimer's disease ͉ paired helical filaments ͉ Tau protein ͉ frontotemporal dementia T he neurofibrillary pathology, based on the aggregation of tau protein into paired helical filaments (PHFs), is a hallmark of Alzheimer's disease (AD) and other tauopathies (1), and the distribution of tau deposits correlates with the loss of neurons (2). The discovery that mutations in the tau gene cause frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP17) (3) and tau aggregation provided evidence that abnormalities in tau were sufficient to cause neurodegeneration. Despite the development of transgenic mice that recapitulate some of the hallmarks of AD (4, 5), the mechanism of tau aggregation remains enigmatic.Tau is a natively unfolded protein that shows little tendency to aggregate in physiological buffers (6). However, aggregation can be dramatically accelerated by polyanionic cofactors such as sulfated glycosaminoglycans, RNA, acidic peptides, or fatty acid micelles (7-10). The aggregation is thought to follow a nucleation-elongation pathway (11), whereby an oligomeric nucleus is first formed by self-association of protein subunits, followed by addition of subunits to filament ends. However, several issues remain open in this scheme: (i) Although tau fragments aggregate spontaneously (12), full-length tau is difficult to fibrillize even at high concentration unless aided by polyanions. (ii) Seeding of recombinant tau with Alzheimer PHFs is inefficient without fibrillization inducers. (iii) The nature of the nucleating species of tau fibrils is not known.A further unsolved question is whether tau aggregation is cytotoxic. Because the occurrence of PHFs correlates with the loss of cognitive functions in AD, it is widely assumed that PHFs are one of the causes of neurodegeneration. On the other hand, neurons bearing PHFs can survive for a long time, and memory deficits in transgenic mice can occur indep...

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Ligand-Dependent Tau Filament Formation: Implications for Alzheimer's Disease Progression

Cited by 142 publications

References 47 publications

Anionic Micelles and Vesicles Induce Tau Fibrillization in Vitro

Anionic Micelles and Vesicles Induce Tau Fibrillization in Vitro

Rapid Anionic Micelle-mediated α-Synuclein Fibrillization in Vitro

Stepwise proteolysis liberates tau fragments that nucleate the Alzheimer-like aggregation of full-length tau in a neuronal cell model

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