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

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 in...

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Published in:	Cellular and molecular life sciences : CMLS 2015-12, Vol.72 (23), p.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:	Article
Language:	eng
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 Disease Models, Animal Electrophysiology - methods glutamic acid hippocampus Hippocampus - cytology Hippocampus - drug effects Hippocampus - metabolism Humans Kinases learning Learning Disorders - 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
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Summary:	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
ISSN:	1420-682X 1420-9071