Polymeric alkylpyridinium salts permit intracellular delivery of human Tau in rat hippocampal neurons: requirement of Tau phosphorylation for functional deficits

Dave J. Koss, Lianne Robinson, Anna Mietelska-Porowska, Anna Gasiorowska, Kristina Sepcic, Tom Turk, Marcel Jaspars, Grazyna Niewiadomska, Roderick H. Scott, Bettina Platt, Gernot Riedel*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

6 Citations (Scopus)

Abstract

Patients suffering from tauopathies including frontotemporal dementia (FTD) and Alzheimer's disease (AD) present with intra-neuronal aggregation of microtubule-associated protein Tau. During the disease process, Tau undergoes excessive phosphorylation, dissociates from microtubules and aggregates into insoluble neurofibrillary tangles (NFTs), accumulating in the soma. While many aspects of the disease pathology have been replicated in transgenic mouse models, a region-specific non-transgenic expression model is missing. Complementing existing models, we here report a novel region-specific approach to modelling Tau pathology. Local co-administration of the pore-former polymeric 1,3-alkylpyridinium salts (Poly-APS) extracted from marine sponges, and synthetic full-length 4R recombinant human Tau (hTau) was performed in vitro and in vivo. At low doses, Poly-APS was non-toxic and cultured cells exposed to Poly-APS (0.5 A mu g/ml) and hTau (1 A mu g/ml; similar to 22 A mu M) had normal input resistance, resting-state membrane potentials and Ca2+ transients induced either by glutamate or KCl, as did cells exposed to a low concentration of the phosphatase inhibitor Okadaic acid (OA; 1 nM, 24 h). Combined hTau loading and phosphatase inhibition resulted in a collapse of the membrane potential, suppressed excitation and diminished glutamate and KCl-stimulated Ca2+ transients. Stereotaxic infusions of Poly-APS (0.005 A mu g/ml) and hTau (1 A mu g/ml) bilaterally into the dorsal hippocampus at multiple sites resulted in hTau loading of neurons in rats. A separate cohort received an additional 7-day minipump infusion of OA (1.2 nM) intrahippocampally. When tested 2 weeks after surgery, rats treated with Poly-APS+hTau+OA presented with subtle learning deficits, but were also impaired in cognitive flexibility and recall. Hippocampal plasticity recorded from slices ex vivo was diminished in Poly-APS+hTau+OA subjects, but not in other treatment groups. Histological sections confirmed the intracellular accumulation of hTau in CA1 pyramidal cells and along their processes; phosphorylated Tau was present only within somata. This study demonstrates that cognitive, physiological and pathological symptoms reminiscent of tauopathies can be induced following non-mutant hTau delivery into CA1 in rats, but functional consequences hinge on increased Tau phosphorylation. Collectively, these data validate a novel model of locally infused recombinant hTau protein as an inducer of Tau pathology in the hippocampus of normal rats; future studies will provide insights into the pathological spread and maturation of Tau pathology.

Original languageEnglish
Pages (from-to)4613-4632
Number of pages20
JournalCellular and Molecular Life Sciences
Volume72
Issue number23
Early online date13 Jun 2015
DOIs
Publication statusPublished - Dec 2015

Keywords

  • Alzheimer's disease
  • frontotemporal dementia
  • tauopathies
  • phospho-Tau
  • Poly-APS
  • Tau
  • LTP
  • calcium
  • protein phosphatase 2A
  • sponge reniera-sarai
  • paired helical filaments
  • familial-frontotemporal-dementia
  • long-term potentiation
  • Alzheimers-Disease
  • okadaic acid
  • marine-sponge
  • spatial memory
  • mouse model

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