title: Intraneuronal accumulation of misfolded tau protein induces overexpression of Hsp27 in activated astrocytes.
abstract: Accumulation of misfolded forms of microtubule associated, neuronal protein tau causes neurofibrillary degeneration typical of Alzheimer's disease and other tauopathies. This process is accompanied by elevated cellular stress and concomitant deregulation of heat-shock proteins. We used a transgenic rat model of tauopathy to study involvement of heat shock protein 27 (Hsp27) in the process of neurofibrillary degeneration, its cell type specific expression and correlation with the amount of insoluble tau protein aggregates. The expression of Hsp27-mRNA is more than doubled and levels of Hsp27 protein tripled in aged transgenic animals with tau pathology. The data revealed a strong positive and highly significant correlation between Hsp27-mRNA and amount of sarkosyl insoluble tau. Interestingly, intracellular accumulation of insoluble misfolded tau protein in neurons was associated with overexpression of Hsp27 almost exclusively in reactive astrocytes, not in neurons. The topological dissociation of neuronally expressed pathological tau and the induction of astrocytic Hsp27, GFAP, and Vimentin along with up-regulation of microglia specific markers such as CD18, CD68 and C3 point to cooperation of astrocytes, microglia and neurons in response to intra-neuronal accumulation of insoluble tau. Our data suggest that over expression of Hsp27 represents a part of microglia-mediated astrocytic response mechanism in the process of neurofibrillary degeneration, which is not necessarily associated with neuroprotection and which in contrary may accelerate neurodegeneration in late stage of the disease. This phenomenon should be considered during development of disease modifying strategies for treatment of tauopathies and AD via regulation of activity of Hsp27.
authors.affiliation: Institute of Neuroimmunology, Slovak Academy of Sciences, Dubravska cesta 9, 84510 Bratislava, Slovakia; Axon Neuroscience SE, Bratislava, Slovakia.
authors.forename: Peter
authors.initials: P
authors.lastname: Filipcik
authors.affiliation: Institute of Neuroimmunology, Slovak Academy of Sciences, Dubravska cesta 9, 84510 Bratislava, Slovakia; Axon Neuroscience SE, Bratislava, Slovakia.
authors.forename: Martin
authors.initials: M
authors.lastname: Cente
authors.affiliation: Institute of Neuroimmunology, Slovak Academy of Sciences, Dubravska cesta 9, 84510 Bratislava, Slovakia; Axon Neuroscience SE, Bratislava, Slovakia.
authors.forename: Norbert
authors.initials: N
authors.lastname: Zilka
authors.affiliation: Institute of Neuroimmunology, Slovak Academy of Sciences, Dubravska cesta 9, 84510 Bratislava, Slovakia; Axon Neuroscience SE, Bratislava, Slovakia.
authors.forename: Tomas
authors.initials: T
authors.lastname: Smolek
authors.affiliation: Axon Neuroscience SE, Bratislava, Slovakia.
authors.forename: Jozef
authors.initials: J
authors.lastname: Hanes
authors.affiliation: Institute of Neuroimmunology, Slovak Academy of Sciences, Dubravska cesta 9, 84510 Bratislava, Slovakia; Axon Neuroscience SE, Bratislava, Slovakia.
authors.forename: Juraj
authors.initials: J
authors.lastname: Kucerak
authors.affiliation: Institute of Neuroimmunology, Slovak Academy of Sciences, Dubravska cesta 9, 84510 Bratislava, Slovakia.
authors.forename: Alena
authors.initials: A
authors.lastname: Opattova
authors.affiliation: Institute of Neuroimmunology, Slovak Academy of Sciences, Dubravska cesta 9, 84510 Bratislava, Slovakia; Axon Neuroscience SE, Bratislava, Slovakia.
authors.forename: Branislav
authors.initials: B
authors.lastname: Kovacech
authors.affiliation: Institute of Neuroimmunology, Slovak Academy of Sciences, Dubravska cesta 9, 84510 Bratislava, Slovakia; Axon Neuroscience SE, Bratislava, Slovakia. Electronic address: michal.novak@savba.sk.
authors.forename: Michal
authors.initials: M
authors.lastname: Novak
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism*; D002478:Cells, Cultured; D005904:Glial Fibrillary Acidic Protein / Q000235:genetics / Q000378:metabolism; D055551:HSP27 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D009474:Neurons / Q000378:metabolism*; D017510:Protein Folding; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D024801:Tauopathies / Q000378:metabolism*; D014746:Vimentin / Q000235:genetics / Q000378:metabolism; D016875:tau Proteins / Q000737:chemistry / Q000378:metabolism*
chemical_list: D005904:Glial Fibrillary Acidic Protein; D055551:HSP27 Heat-Shock Proteins; C486114:Hspb1 protein, rat; C054369:MAPT protein, human; D012333:RNA, Messenger; D014746:Vimentin; D016875:tau Proteins
keywords: Alzheimer's disease; Astrocyte; Hsp27; Tauopathy; Transgenic rat; Truncated tau protein