Autophagic-lysosomal perturbation enhances tau aggregation in transfectants with induced wild-type tau expression

Abstract Accumulation of assembled tau protein in the central nervous system is characteristic of Alzheimer’s disease and several other neurodegenerative diseases, called tauopathies. Recent studies have revealed that propagation of assembled tau is key to understanding the pathological mechanisms of these diseases. Mouse models of tau propagation are established by injecting human-derived tau seeds intracerebrally; nevertheless, these have a limitation in terms of regulation of availability. To date, no study has shown that synthetic assembled tau induce tau propagation in non-transgenic mice. Here we confirm that dextran sulphate, a sulphated glycosaminoglycan, induces the assembly of recombinant tau protein into filaments in vitro. As compared to tau filaments induced by heparin, those induced by dextran sulphate showed higher thioflavin T fluorescence and lower resistance to guanidine hydrochloride, which suggests that the two types of filaments have distinct conformational features. Unlike other synthetic filament seeds, intracerebral injection of dextran sulphate-induced assemblies of recombinant tau caused aggregation of endogenous murine tau in wild-type mice. AT8-positive tau was present at the injection site 1 month after injection, from where it spread to anatomically connected regions. Induced tau assemblies were also stained by anti-tau antibodies AT100, AT180, 12E8, PHF1, anti-pS396 and anti-pS422. They were thioflavin- and Gallyas-Braak silver-positive, indicative of amyloid. In biochemical analyses, accumulated sarkosyl-insoluble and hyperphosphorylated tau was observed in the injected mice. In conclusion, we revealed that intracerebral injection of synthetic full-length wild-type tau seeds prepared in the presence of dextran sulphate caused tau propagation in non-transgenic mice. These findings establish that propagation of tau assemblies does not require tau to be either mutant and/or overexpressed.

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Mechanisms of Anticholinesterase Interference with Tau Aggregation Inhibitor Activity in a Tau-Transgenic Mouse Model

Current Alzheimer Research ◽

10.2174/1567205017666200224120926 ◽

2020 ◽

Vol 17 (3) ◽

pp. 285-296 ◽

Cited By ~ 5

Author(s):

Gernot Riedel ◽

Jochen Klein ◽

Grazyna Niewiadomska ◽

Constantin Kondak ◽

Karima Schwab ◽

...

Keyword(s):

Mouse Model ◽

Glutamate Release ◽

Symptomatic Treatment ◽

Transgenic Mouse Model ◽

Wild Type ◽

Mitochondrial Complex ◽

Tau Pathology ◽

Complex Iv ◽

Aggregation Inhibitor ◽

Tau Aggregation

Background: Symptomatic treatments of Alzheimer’s Disease (AD) with cholinesterase inhibitors and/or memantine are relatively ineffective and there is a need for new treatments targeting the underlying pathology of AD. In most of the failed disease-modifying trials, patients have been allowed to continue taking symptomatic treatments at stable doses, under the assumption that they do not impair efficacy. In recently completed Phase 3 trials testing the tau aggregation inhibitor leuco-methylthioninium bis (hydromethanesulfonate) (LMTM), we found significant differences in treatment response according to whether patients were taking LMTM either as monotherapy or as an add-on to symptomatic treatments. Methods: We have examined the effect of either LMTM alone or chronic rivastigmine prior to LMTM treatment of tau transgenic mice expressing the short tau fragment that constitutes the tangle filaments of AD. We have measured acetylcholine levels, synaptosomal glutamate release, synaptic proteins, mitochondrial complex IV activity, tau pathology and Choline Acetyltransferase (ChAT) immunoreactivity. Results: LMTM given alone increased hippocampal Acetylcholine (ACh) levels, glutamate release from synaptosomal preparations, synaptophysin levels in multiple brain regions and mitochondrial complex IV activity, reduced tau pathology, partially restored ChAT immunoreactivity in the basal forebrain and reversed deficits in spatial learning. Chronic pretreatment with rivastigmine was found to reduce or eliminate almost all these effects, apart from a reduction in tau aggregation pathology. LMTM effects on hippocampal ACh and synaptophysin levels were also reduced in wild-type mice. Conclusion: The interference with the pharmacological activity of LMTM by a cholinesterase inhibitor can be reproduced in a tau transgenic mouse model and, to a lesser extent, in wild-type mice. Long-term pretreatment with a symptomatic drug alters a broad range of brain responses to LMTM across different transmitter systems and cellular compartments at multiple levels of brain function. There is, therefore, no single locus for the negative interaction. Rather, the chronic neuronal activation induced by reducing cholinesterase function produces compensatory homeostatic downregulation in multiple neuronal systems. This reduces a broad range of treatment responses to LMTM associated with a reduction in tau aggregation pathology. Since the interference is dictated by homeostatic responses to prior symptomatic treatment, it is likely that there would be similar interference with other drugs tested as add-on to the existing symptomatic treatment, regardless of the intended therapeutic target or mode of action. The present findings outline key results that now provide a working model to explain interference by symptomatic treatment.

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Modulation of tau pathology in tau transgenic models

Biochemical Society Transactions ◽

10.1042/bst0380996 ◽

2010 ◽

Vol 38 (4) ◽

pp. 996-1000 ◽

Cited By ~ 8

Author(s):

Jean-Pierre Brion ◽

Kunie Ando ◽

Céline Heraud ◽

Karelle Leroy

Keyword(s):

Neuronal Death ◽

Amyloid Β ◽

Tau Proteins ◽

Amyloid Β Peptide ◽

Wild Type ◽

Tau Pathology ◽

Amyloid Pathology ◽

Aβ Amyloid ◽

Tau Aggregation ◽

The Relationship

NFTs (neurofibrillary tangles) in Alzheimer's disease and in tauopathies are hallmark neuropathological lesions whose relationship with neuronal dysfunction, neuronal death and with other lesions [such as Aβ (amyloid β-peptide) pathology] are still imperfectly understood. Many transgenic mice overexpressing wild-type or mutant tau proteins have been generated to investigate the physiopathology of tauopathies. Most of the mice overexpressing wild-type tau do not develop NFTs, but can develop a severe axonopathy, whereas overexpression of mutant tau leads to NFT formation, synaptic loss and neuronal death in several models. The association between neuronal death and NFTs has, however, been challenged in some models showing a dissociation between tau aggregation and tau toxicity. Cross-breeding of mice developing NFTs with mice developing Aβ deposits increases NFT pathology, highlighting the relationship between tau and amyloid pathology. On the other hand, tau expression seems to be necessary for expression of a pathological phenotype associated with amyloid pathology. These findings suggest that there is a bilateral cross-talk between Aβ and tau pathology. These observations are discussed by the presentation of some relevant models developed recently.

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Hsp90 co-chaperones, FKBP52 and Aha1, promote tau pathogenesis in aged wild-type mice

Acta Neuropathologica Communications ◽

10.1186/s40478-021-01159-w ◽

2021 ◽

Vol 9 (1) ◽

Author(s):

Marangelie Criado-Marrero ◽

Niat T. Gebru ◽

Danielle M. Blazier ◽

Lauren A. Gould ◽

Jeremy D. Baker ◽

...

Keyword(s):

Neuronal Loss ◽

Hippocampal Volume ◽

Brain Regions ◽

Aging Brain ◽

Protein Homeostasis ◽

Wild Type ◽

Fk506 Binding Protein ◽

Intrinsically Disordered ◽

Tau Aggregation

AbstractThe microtubule associated protein tau is an intrinsically disordered phosphoprotein that accumulates under pathological conditions leading to formation of neurofibrillary tangles, a hallmark of Alzheimer’s disease (AD). The mechanisms that initiate the accumulation of phospho-tau aggregates and filamentous deposits are largely unknown. In the past, our work and others’ have shown that molecular chaperones play a crucial role in maintaining protein homeostasis and that imbalance in their levels or activity can drive tau pathogenesis. We have found two co-chaperones of the 90 kDa heat shock protein (Hsp90), FK506-binding protein 52 (FKBP52) and the activator of Hsp90 ATPase homolog 1 (Aha1), promote tau aggregation in vitro and in the brains of tau transgenic mice. Based on this, we hypothesized that increased levels of these chaperones could promote tau misfolding and accumulation in the brains of aged wild-type mice. We tested this hypothesis by overexpressing Aha1, FKBP52, or mCherry (control) proteins in the hippocampus of 9-month-old wild-type mice. After 7 months of expression, mice were evaluated for cognitive and pathological changes. Our results show that FKBP52 overexpression impaired spatial reversal learning, while Aha1 overexpression impaired associative learning in aged wild-type mice. FKBP52 and Aha1 overexpression promoted phosphorylation of distinct AD-relevant tau species. Furthermore, FKBP52 activated gliosis and promoted neuronal loss leading to a reduction in hippocampal volume. Glial activation and phospho-tau accumulation were also detected in areas adjacent to the hippocampus, including the entorhinal cortex, suggesting that after initiation these pathologies can propagate through other brain regions. Overall, our findings suggest a role for chaperone imbalance in the initiation of tau accumulation in the aging brain.

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DnaJC7 binds natively folded structural elements in tau to inhibit amyloid formation

10.1101/2020.12.15.422895 ◽

2020 ◽

Author(s):

Zhiqiang Hou ◽

Pawel M Wydorski ◽

Valerie A Perez ◽

Ayde Mendoza-Oliva ◽

Bryan D Ryder ◽

...

Keyword(s):

Molecular Chaperones ◽

Therapeutic Intervention ◽

Amyloid Formation ◽

Structural Elements ◽

Wild Type ◽

Beta Turn ◽

Chaperone Binding ◽

Tau Aggregation ◽

Tpr Domain

Molecular chaperones, including Hsp70/Hsp40 families, play central roles in binding substrates to prevent their aggregation. How Hsp40s select different conformations of substrates remains poorly understood. Here, we report a novel interaction between the Hsp40 DnaJC7 and tau that efficiently suppresses tau aggregation in vitro and in cells. DnaJC7 binds preferentially to natively folded wild-type tau, but disease-associated mutants in tau reduce chaperone binding affinity. We identify that DnaJC7 uses a single TPR domain to recognize a beta-turn element in tau that contains the 275VQIINK280 amyloid motif. Wild-type tau beta-turn fragments, but not mutant fragments, can block full-length tau binding to DnaJC7. These data suggest DnaJC7 preferentially binds and stabilizes natively folded conformations of tau to prevent tau conversion into amyloids. This identifies a novel mechanism of tau aggregation regulation that can be exploited as both a diagnostic and a therapeutic intervention.

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DnaJC7 binds natively folded structural elements in tau to inhibit amyloid formation

10.21203/rs.3.rs-129204/v1 ◽

2021 ◽

Author(s):

Lukasz Joachimiak ◽

Zhiqiang Hou ◽

Pawel Wydorski ◽

Valerie Perez ◽

Ayde Mendoza-Oliva ◽

...

Keyword(s):

Binding Affinity ◽

Molecular Chaperones ◽

Therapeutic Intervention ◽

Amyloid Formation ◽

Structural Elements ◽

Wild Type ◽

Chaperone Binding ◽

Tau Aggregation ◽

Tpr Domain

Abstract Molecular chaperones, including Hsp70/Hsp40 families, play central roles in binding substrates to prevent their aggregation. How Hsp40s select different conformations of substrates remains poorly understood. Here, we report a novel interaction between the Hsp40 DnaJC7 and tau that efficiently suppresses tau aggregation in vitro and in cells. DnaJC7 binds preferentially to natively folded wild-type tau, but disease-associated mutants in tau reduce chaperone binding affinity. We identify that DnaJC7 uses a single TPR domain to recognize a β-turn element in tau that contains the 275VQIINK280 amyloid motif. Wild-type tau β-turn fragments, but not mutant fragments, can block full-length tau binding to DnaJC7. These data suggest DnaJC7 preferentially binds and stabilizes natively folded conformations of tau to prevent tau conversion into amyloids. This identifies a novel mechanism of tau aggregation regulation that can be exploited as both a diagnostic and a therapeutic intervention.

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Human P301L-Mutant Tau Expression in Mouse Entorhinal-Hippocampal Network Causes Tau Aggregation and Presynaptic Pathology but No Cognitive Deficits

PLoS ONE ◽

10.1371/journal.pone.0045881 ◽

2012 ◽

Vol 7 (9) ◽

pp. e45881 ◽

Cited By ~ 79

Author(s):

Julie A. Harris ◽

Akihiko Koyama ◽

Sumihiro Maeda ◽

Kaitlyn Ho ◽

Nino Devidze ◽

...

Keyword(s):

Cognitive Deficits ◽

Hippocampal Network ◽

Tau Aggregation ◽

Tau Expression

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O3-01-01: A NEW MOUSE MODEL WITH HUMANIZED WILD-TYPE TAU EXPRESSION

Alzheimer s & Dementia ◽

10.1016/j.jalz.2018.06.2770 ◽

2006 ◽

Vol 14 (7S_Part_18) ◽

pp. P1008-P1008

Author(s):

Holger Cynis ◽

Susan Barendrecht ◽

Detlef Balschun ◽

Stephan Schilling ◽

Hans-Ulrich Demuth

Keyword(s):

Mouse Model ◽

Wild Type ◽

Tau Expression

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DnaJC7 binds natively folded structural elements in tau to inhibit amyloid formation

Nature Communications ◽

10.1038/s41467-021-25635-y ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Zhiqiang Hou ◽

Pawel M. Wydorski ◽

Valerie A. Perez ◽

Aydé Mendoza-Oliva ◽

Bryan D. Ryder ◽

...

Keyword(s):

Molecular Chaperones ◽

Amyloid Formation ◽

Structural Elements ◽

Wild Type ◽

Structural Element ◽

Chaperone Binding ◽

J Domain ◽

Tau Aggregation ◽

Tpr Domain

AbstractMolecular chaperones, including Hsp70/J-domain protein (JDP) families, play central roles in binding substrates to prevent their aggregation. How JDPs select different conformations of substrates remains poorly understood. Here, we report an interaction between the JDP DnaJC7 and tau that efficiently suppresses tau aggregation in vitro and in cells. DnaJC7 binds preferentially to natively folded wild-type tau, but disease-associated mutants in tau reduce chaperone binding affinity. We identify that DnaJC7 uses a single TPR domain to recognize a β-turn structural element in tau that contains the 275VQIINK280 amyloid motif. Wild-type tau, but not mutant, β-turn structural elements can block full-length tau binding to DnaJC7. These data suggest DnaJC7 preferentially binds and stabilizes natively folded conformations of tau to prevent tau conversion into amyloids. Our work identifies a novel mechanism of tau aggregation regulation that can be exploited as both a diagnostic and a therapeutic intervention.

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In vitro tau aggregation inducer molecules influence the effects of MAPT mutations on aggregation dynamics

10.1101/2021.08.06.455436 ◽

2021 ◽

Author(s):

David J Ingham ◽

Kelsey M Hillyer ◽

Madison J McGuire ◽

Truman Christopher Gamblin

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Health Care Cost ◽

In Vitro Studies ◽

Chromosome 17 ◽

Wild Type ◽

Different Strains ◽

Tau Aggregation ◽

Frontotemporal Dementias

Alzheimer's disease (AD) and Alzheimer's disease related dementias (ADRDs) affect 6 million Americans and they are projected to have an estimated health care cost of $355 billion for 2021. A histopathological hallmark of AD and many ADRDs is the aberrant intracellular accumulation of the microtubule associated protein tau. These neurodegenerative disorders that contain tau aggregates are collectively known as tauopathies and recent structural studies have shown that different tauopathies are characterized by different "strains" of tau filaments. In addition, mutations in the gene that encodes for tau protein expression have been associated with a group of tauopathies known as frontotemporal dementias with Parkinsonism linked to chromosome 17 (FTDP-17 or familial frontotemporal dementia). In vitro studies often use small molecules to induce tau aggregation as tau is extremely soluble and does not spontaneously aggregate in typical lab conditions and the use of authentic filaments to conduct in vitro studies is not feasible. This study highlights how different inducer molecules can have fundamental disparities to how disease related mutations effect the aggregation dynamics of tau. Using three different classes of tau aggregation inducer molecules we characterized disease relevant mutations in tau's PGGG motifs at positions P301S, P332S, and P364S. When comparing these mutations to wild type tau, we found that depending on the type of inducer molecule used we saw fundamental differences in total aggregation, aggregation kinetics, immunoreactivity, and filament morphology. These data support the hypothesis that different tau aggregation inducer molecules make different polymorphs and perhaps structurally distinct strains.

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