Pore-former enabled seeding of tau in rats

Alleviation by memantine and lithium chloride

Anna Mietelska-Porowska, Anna Gasiorowska, Ewelina Palasz, Dave J Koss, Gernot Riedel, Grazyna Niewiadomska (Corresponding Author)

Research output: Contribution to journalArticle

Abstract

Background Tauopathies, including Alzheimer's disease (AD), are multifactorial diseases with strong phenotypic and genetic heterogeneity. Recent evidence revealed that mechanisms of pathogenesis of early (hereditary) and late (sporadic) forms of AD are different. This is not properly reflected in current experimental models, especially when it comes to sporadic forms of AD. Here, we present novel seeding based model and explore its suitability for therapeutic intervention. New method We validate novel region specific approach to modelling Tau pathology reported by Koss and co-authors (2015). Wistar rats 3, 9 and 15 month-old were surgically prepared for hippocampal loading with pore-former polymeric 1,3-alkylpyridinium salts (Poly-APS) and recombinant human tau including pharmacological inhibition of phosphatase activity by okadaic acid co-administration. We explored whether tau seeding caused molecular and behavioural traits reminiscent of AD and explored their reversibility/prevention by administration of either memantine or lithium. Results The presented model emulates several changes observed in progressive dementia such as: heightened levels of tau and its hyperphosphorylation, changes in tau compartmentalization, breakdown of the cytoskeleton, cognitive impairments, and sensitivity for anti-dementia treatment. Comparison with existing methods Seeding has been achieved in transgenic mouse models, but this is the first rat model significantly mimicking cognitive and neuronal changes akin to tauopathies. Moreover, we have successfully included the factor age in our model and can show sensitivity to drug treatment. Conclusions These data validate a novel model of locally infused recombinant human Tau as an inducer of tauopathy in rats and holds the potential for development of novel therapies.

Original languageEnglish
Pages (from-to)47-59
Number of pages13
JournalJournal of Neuroscience Methods
Volume319
Early online date16 Nov 2018
DOIs
Publication statusPublished - 1 May 2019

Fingerprint

Memantine
Lithium Chloride
Tauopathies
Alzheimer Disease
Dementia
Okadaic Acid
Genetic Heterogeneity
Age Factors
Cytoskeleton
Lithium
Phosphoric Monoester Hydrolases
Transgenic Mice
Wistar Rats
Theoretical Models
Pharmacology
Pathology
Therapeutics
Pharmaceutical Preparations

Keywords

  • tauopathies
  • Alzheimer’s disease
  • Tau and phospho-Tau
  • Poly-APS
  • cytoskeleton
  • Memantine
  • Lithium Chloride
  • Hippocampal CA1 area
  • spatial learning

Cite this

Pore-former enabled seeding of tau in rats : Alleviation by memantine and lithium chloride. / Mietelska-Porowska, Anna; Gasiorowska, Anna; Palasz, Ewelina; Koss, Dave J; Riedel, Gernot; Niewiadomska, Grazyna (Corresponding Author).

In: Journal of Neuroscience Methods, Vol. 319, 01.05.2019, p. 47-59.

Research output: Contribution to journalArticle

Mietelska-Porowska, Anna ; Gasiorowska, Anna ; Palasz, Ewelina ; Koss, Dave J ; Riedel, Gernot ; Niewiadomska, Grazyna. / Pore-former enabled seeding of tau in rats : Alleviation by memantine and lithium chloride. In: Journal of Neuroscience Methods. 2019 ; Vol. 319. pp. 47-59.
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abstract = "Background Tauopathies, including Alzheimer's disease (AD), are multifactorial diseases with strong phenotypic and genetic heterogeneity. Recent evidence revealed that mechanisms of pathogenesis of early (hereditary) and late (sporadic) forms of AD are different. This is not properly reflected in current experimental models, especially when it comes to sporadic forms of AD. Here, we present novel seeding based model and explore its suitability for therapeutic intervention. New method We validate novel region specific approach to modelling Tau pathology reported by Koss and co-authors (2015). Wistar rats 3, 9 and 15 month-old were surgically prepared for hippocampal loading with pore-former polymeric 1,3-alkylpyridinium salts (Poly-APS) and recombinant human tau including pharmacological inhibition of phosphatase activity by okadaic acid co-administration. We explored whether tau seeding caused molecular and behavioural traits reminiscent of AD and explored their reversibility/prevention by administration of either memantine or lithium. Results The presented model emulates several changes observed in progressive dementia such as: heightened levels of tau and its hyperphosphorylation, changes in tau compartmentalization, breakdown of the cytoskeleton, cognitive impairments, and sensitivity for anti-dementia treatment. Comparison with existing methods Seeding has been achieved in transgenic mouse models, but this is the first rat model significantly mimicking cognitive and neuronal changes akin to tauopathies. Moreover, we have successfully included the factor age in our model and can show sensitivity to drug treatment. Conclusions These data validate a novel model of locally infused recombinant human Tau as an inducer of tauopathy in rats and holds the potential for development of novel therapies.",
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author = "Anna Mietelska-Porowska and Anna Gasiorowska and Ewelina Palasz and Koss, {Dave J} and Gernot Riedel and Grazyna Niewiadomska",
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T2 - Alleviation by memantine and lithium chloride

AU - Mietelska-Porowska, Anna

AU - Gasiorowska, Anna

AU - Palasz, Ewelina

AU - Koss, Dave J

AU - Riedel, Gernot

AU - Niewiadomska, Grazyna

N1 - Acknowledgements: This work was funded by NCN grant2014/15/B/NZ4/05041 and TauRx Therapeutics/WisTa Laboratories Ltd., Singapore and by statutory funds from the Nencki Institute of Experimental Biology.

PY - 2019/5/1

Y1 - 2019/5/1

N2 - Background Tauopathies, including Alzheimer's disease (AD), are multifactorial diseases with strong phenotypic and genetic heterogeneity. Recent evidence revealed that mechanisms of pathogenesis of early (hereditary) and late (sporadic) forms of AD are different. This is not properly reflected in current experimental models, especially when it comes to sporadic forms of AD. Here, we present novel seeding based model and explore its suitability for therapeutic intervention. New method We validate novel region specific approach to modelling Tau pathology reported by Koss and co-authors (2015). Wistar rats 3, 9 and 15 month-old were surgically prepared for hippocampal loading with pore-former polymeric 1,3-alkylpyridinium salts (Poly-APS) and recombinant human tau including pharmacological inhibition of phosphatase activity by okadaic acid co-administration. We explored whether tau seeding caused molecular and behavioural traits reminiscent of AD and explored their reversibility/prevention by administration of either memantine or lithium. Results The presented model emulates several changes observed in progressive dementia such as: heightened levels of tau and its hyperphosphorylation, changes in tau compartmentalization, breakdown of the cytoskeleton, cognitive impairments, and sensitivity for anti-dementia treatment. Comparison with existing methods Seeding has been achieved in transgenic mouse models, but this is the first rat model significantly mimicking cognitive and neuronal changes akin to tauopathies. Moreover, we have successfully included the factor age in our model and can show sensitivity to drug treatment. Conclusions These data validate a novel model of locally infused recombinant human Tau as an inducer of tauopathy in rats and holds the potential for development of novel therapies.

AB - Background Tauopathies, including Alzheimer's disease (AD), are multifactorial diseases with strong phenotypic and genetic heterogeneity. Recent evidence revealed that mechanisms of pathogenesis of early (hereditary) and late (sporadic) forms of AD are different. This is not properly reflected in current experimental models, especially when it comes to sporadic forms of AD. Here, we present novel seeding based model and explore its suitability for therapeutic intervention. New method We validate novel region specific approach to modelling Tau pathology reported by Koss and co-authors (2015). Wistar rats 3, 9 and 15 month-old were surgically prepared for hippocampal loading with pore-former polymeric 1,3-alkylpyridinium salts (Poly-APS) and recombinant human tau including pharmacological inhibition of phosphatase activity by okadaic acid co-administration. We explored whether tau seeding caused molecular and behavioural traits reminiscent of AD and explored their reversibility/prevention by administration of either memantine or lithium. Results The presented model emulates several changes observed in progressive dementia such as: heightened levels of tau and its hyperphosphorylation, changes in tau compartmentalization, breakdown of the cytoskeleton, cognitive impairments, and sensitivity for anti-dementia treatment. Comparison with existing methods Seeding has been achieved in transgenic mouse models, but this is the first rat model significantly mimicking cognitive and neuronal changes akin to tauopathies. Moreover, we have successfully included the factor age in our model and can show sensitivity to drug treatment. Conclusions These data validate a novel model of locally infused recombinant human Tau as an inducer of tauopathy in rats and holds the potential for development of novel therapies.

KW - tauopathies

KW - Alzheimer’s disease

KW - Tau and phospho-Tau

KW - Poly-APS

KW - cytoskeleton

KW - Memantine

KW - Lithium Chloride

KW - Hippocampal CA1 area

KW - spatial learning

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JO - Journal of Neuroscience Methods

JF - Journal of Neuroscience Methods

SN - 0165-0270

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