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

• Published in: Cellular and molecular life sciences : CMLS Vol. 72; no. 23; pp. 4613 - 4632
• Main Authors: Koss, Dave J, Robinson, Lianne, Mietelska-Porowska, Anna, Gasiorowska, Anna, Sepčić, Kristina, Turk, Tom, Jaspars, Marcel, Niewiadomska, Grazyna, Scott, Roderick H, Platt, Bettina, Riedel, Gernot
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 01.12.2015; Springer Nature B.V
• Subjects: Alzheimer disease; Alzheimer's disease; animal models; Animals; Behavior, Animal - drug effects; Biochemistry; Biomedical and Life Sciences; Biomedicine; calcium; Calcium Signaling - drug effects; Cell Biology; Cells, Cultured; cognition; cultured cells; Dementia; Dementia disorders; Disease Models, Animal; Electrophysiology - methods; glutamic acid; hippocampus; Hippocampus - cytology; Hippocampus - drug effects; Hippocampus - metabolism; Humans; Kinases; learning; Learning Disabilities - drug therapy; Life Sciences; Male; membrane potential; microtubules; Mutation; Neuronal Plasticity - physiology; neurons; Neurons - drug effects; Neurons - metabolism; Neurons - physiology; Neurosciences; okadaic acid; Pathology; patients; Phosphatase; Phosphorylation; Polymers - administration & dosage; Polymers - pharmacology; Porifera; potassium chloride; Proteins; Pyridinium Compounds - administration & dosage; Pyridinium Compounds - pharmacology; rats; Rats, Sprague-Dawley; Recombinant Proteins - administration & dosage; Recombinant Proteins - metabolism; Recombinant Proteins - pharmacology; Research Article; surgery; tau Proteins - administration & dosage; tau Proteins - metabolism; tau Proteins - pharmacology; Tauopathies - metabolism; transgenic animals; United Kingdom > UK; Poland; Tauopathies; Phospho-Tau; Alzheimer’s disease; Calcium; Poly-APS; Tau; LTP; Frontotemporal dementia
• ISSN: 1420-682X; 1420-9071; 1420-9071
• DOI: 10.1007/s00018-015-1949-4

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 µg/ml) and hTau (1 µg/ml; ~22 µM) 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 µg/ml) and hTau (1 µg/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.