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Intraneuronal Tau Misfolding Induced by Extracellular Amyloid-? Oligomers.

ABSTRACT: Abnormal folding and aggregation of the microtubule-associated protein, tau, is a hallmark of several neurodegenerative disorders, including Alzheimer's disease (AD). Although normal tau is an intrinsically disordered protein, it does exhibit tertiary structure whereby the N- and C-termini are often in close proximity to each other and to the contiguous microtubule-binding repeat domains that extend C-terminally from the middle of the protein. Unfolding of this paperclip-like conformation might precede formation of toxic tau oligomers and filaments, like those found in AD brain. While there are many ways to monitor tau aggregation, methods to monitor changes in tau folding are not well established. Using full length human 2N4R tau doubly labeled with the Förster resonance energy transfer (FRET) compatible fluorescent proteins, Venus and Teal, on the N- and C-termini, respectively (Venus-Tau-Teal), intensity and lifetime FRET measurements were able to distinguish folded from unfolded tau in living cells independently of tau-tau intermolecular interactions. When expression was restricted to low levels in which tau-tau aggregation was minimized, Venus-Tau-Teal was sensitive to microtubule binding, phosphorylation, and pathogenic oligomers. Of particular interest is our finding that amyloid-? oligomers (A?Os) trigger Venus-Tau-Teal unfolding in cultured mouse neurons. We thus provide direct experimental evidence that A?Os convert normally folded tau into a conformation thought to predominate in toxic tau aggregates. This finding provides further evidence for a mechanistic connection between A? and tau at seminal stages of AD pathogenesis.

SUBMITTER: Rudenko LK

PROVIDER: S-EPMC7464573 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Intraneuronal Tau Misfolding Induced by Extracellular Amyloid-β Oligomers.

Rudenko Lauren K LK Wallrabe Horst H Periasamy Ammasi A Siller Karsten H KH Svindrych Zdenek Z Seward Matthew E ME Best Merci N MN Bloom George S GS

Journal of Alzheimer's disease : JAD 20190101 4

Abnormal folding and aggregation of the microtubule-associated protein, tau, is a hallmark of several neurodegenerative disorders, including Alzheimer's disease (AD). Although normal tau is an intrinsically disordered protein, it does exhibit tertiary structure whereby the N- and C-termini are often in close proximity to each other and to the contiguous microtubule-binding repeat domains that extend C-terminally from the middle of the protein. Unfolding of this paperclip-like conformation might ...[more]

PMID: 31524157

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Project description:Introduction: ?-Amyloid protein (A?) putatively plays a seminal role in synaptic loss in Alzheimer's disease (AD). While there is no consensus regarding the synaptic-relevant species of A?, it is known that A? oligomers (A?Os) are noticeably increased in the early stages of AD, localizing at or within the synapse. In cell and animal models, A?Os have been shown to attach to synapses and instigate synapse dysfunction and deterioration. To establish the pathological mechanism of synaptic loss in AD, it will be important to identify the synaptic targets to which A?Os attach. Methods: An unbiased approach using far western ligand blots has identified three synaptic proteins to which A?Os specifically attach. These proteins (p100, p140, and p260) were subsequently enriched by detergent extraction, ultracentrifugation, and CHT-HPLC column separation, and sequenced by LC-MS/MS. P100, p140, and p260 were identified. These levels of A?Os targets in human AD and aging frontal cortexes were analyzed by quantitative proteomics and western-blot. The polyclonal antibody to A?Os was developed and used to block the toxicity of A?Os. The data were analyzed with one-way analysis of variance. Results: A?Os binding proteins p100, p140, and p260 were identified as Na/K-ATPase, synGap, and Shank3, respectively. ?3-Na/K-ATPase, synGap, and Shank3 proteins showed loss in the postsynaptic density (PSD) of human AD frontal cortex. In short term experiments, oligomers of A? inhibited Na/K-ATPase at the synapse. Na/K-ATPase activity was restored by an antibody specific for soluble forms of A?. ?3-Na/K-ATPase protein and synaptic ?-amyloid peptides were pulled down from human AD synapses by co-immunoprecipitation. Results suggest synaptic dysfunction in early stages of AD may stem from inhibition of Na/K-ATPase activity by A? oligomers, while later stages could hypothetically result from disrupted synapse structure involving the PSD proteins synGap and Shank3. Conclusion: We identified three A?O binding proteins as ?3-Na/K-ATPase, synGap, and Shank3. Soluble A? oligomers appear capable of attacking neurons via specific extracellular as well as intracellular synaptic proteins. Impact on these proteins hypothetically could lead to synaptic dysfunction and loss, and could serve as novel therapeutic targets for AD treatment by antibodies or other agents.

Dataset Information

Intraneuronal Tau Misfolding Induced by Extracellular Amyloid-? Oligomers.

Publications

Intraneuronal Tau Misfolding Induced by Extracellular Amyloid-β Oligomers.

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