title: The neuronal extracellular matrix restricts distribution and internalization of aggregated Tau-protein.
abstract: Alzheimer's disease (AD) is a chronic degenerative disorder characterized by fibrillary aggregates of Aß and Tau-protein. Formation and progression of these pathological hallmarks throughout the brain follow a specific spatio-temporal pattern which provides the basis for neuropathological staging. Previously, we could demonstrate that cortical and subcortical neurons are less frequently affected by neurofibrillary degeneration if they are enwrapped by a specialized form of the hyaluronan-based extracellular matrix (ECM), the so called 'perineuronal net' (PN). PNs are composed of large aggregating chondroitin sulfate proteoglycans connected to a hyaluronan backbone, stabilized by link proteins and cross-linked via tenascin-R. Recently, PN-associated neurons were shown to be better protected against iron-induced neurodegeneration compared to neurons without PN, indicating a neuroprotective function. Here, we investigated the role of PNs in distribution and internalization of exogenous Tau-protein by using organotypic slice cultures of wildtype mice as well as mice lacking the ECM-components aggrecan, HAPLN1 or tenascin-R. We could demonstrate that PNs restrict both distribution and internalization of Tau. Accordingly, PN-ensheathed neurons were less frequently affected by Tau-internalization, than neurons without PN. Finally, the PNs as well as their three investigated components were shown to modulate the processes of distribution as well as internalization of Tau.
authors.affiliation: University of Leipzig, Department for Molecular and Cellular Mechanisms of Neurodegeneration, Paul Flechsig Institute of Brain Research, Liebigstraße 19, 04103 Leipzig, Germany. Electronic address: anne.suttkus@medizin.uni-leipzig.de.
authors.forename: A
authors.initials: A
authors.lastname: Suttkus
authors.affiliation: University of Leipzig, Department for Molecular and Cellular Mechanisms of Neurodegeneration, Paul Flechsig Institute of Brain Research, Liebigstraße 19, 04103 Leipzig, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Holzer
authors.affiliation: University of Leipzig, Department for Molecular and Cellular Mechanisms of Neurodegeneration, Paul Flechsig Institute of Brain Research, Liebigstraße 19, 04103 Leipzig, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Morawski
authors.affiliation: University of Leipzig, Department for Molecular and Cellular Mechanisms of Neurodegeneration, Paul Flechsig Institute of Brain Research, Liebigstraße 19, 04103 Leipzig, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Arendt
mesh_terms: D053674:Aggrecans / Q000235:genetics / Q000378:metabolism; D000818:Animals; D004926:Escherichia coli; D005109:Extracellular Matrix / Q000378:metabolism*; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism; D005260:Female; D006801:Humans; D042541:Intracellular Space / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism*; D055503:Protein Multimerization / Q000502:physiology*; D011509:Proteoglycans / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D013003:Somatosensory Cortex / Q000378:metabolism; D019063:Tenascin / Q000235:genetics / Q000378:metabolism; D046509:Tissue Culture Techniques; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism*; D000099249:Proteoglycan Link Protein
chemical_list: D053674:Aggrecans; D016326:Extracellular Matrix Proteins; D011509:Proteoglycans; D011994:Recombinant Proteins; D019063:Tenascin; D016875:tau Proteins; D000099249:Proteoglycan Link Protein; C054369:MAPT protein, human; C558298:Mapt protein, mouse; C074638:tenascin R
keywords: Alzheimer’s disease; Tau; extracellular matrix; neuroprotection; perineuronal nets; spreading