Pore-former enabled seeding of tau in rats: Alleviation by memantine and lithium chloride

• Published in: Journal of neuroscience methods Vol. 319; pp. 47 - 59
• Main Authors: Mietelska-Porowska, Anna, Gasiorowska, Anna, Palasz, Ewelina, Koss, Dave J., Riedel, Gernot, Niewiadomska, Grazyna
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01-05-2019
• Subjects: Alzheimer’s disease; Cytoskeleton; Hippocampal CA1 area; Lithium chloride; Memantine; Poly-APS; Spatial learning; Tau and phospho-Tau; Tauopathies; Tauopathies; Hippocampal CA1 area; Memantine; Alzheimer’s disease; Lithium chloride; Poly-APS; Cytoskeleton; Tau and phospho-Tau; Spatial learning
• ISSN: 0165-0270; 1872-678X
• DOI: 10.1016/j.jneumeth.2018.11.009

•exogenous hTau441 penetrates the hippocampal cells in presence of Poly-APS neurotoxin.•seeding tau became phosphorylated when okadaic acid was infused to the rat brain.•aged rats are more vulnerable to tau seeding and are impaired in spatial learning.•treatment with lithium chloride or memantine rescues seeding-related phenotypes.•age-dependent seeding induced tauopathy represents truthful model of sporadic human disease.
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.