title: Tau Oligomers Associate with Inflammation in the Brain and Retina of Tauopathy Mice and in Neurodegenerative Diseases.
abstract: It is well-established that inflammation plays an important role in Alzheimer's disease (AD) and frontotemporal lobar dementia (FTLD). Inflammation and synapse loss occur in disease prior to the formation of larger aggregates, but the contribution of tau to inflammation has not yet been thoroughly investigated. Tau pathologically aggregates to form large fibrillar structures known as tangles. However, evidence suggests that smaller soluble aggregates, called oligomers, are the most toxic species and form prior to tangles. Furthermore, tau oligomers can spread to neighboring cells and between anatomically connected brain regions. In addition, recent evidence suggests that inspecting the retina may be a window to brain pathology. We hypothesized that there is a relationship between tau oligomers and inflammation, which are hallmarks of early disease. We conducted immunofluorescence and biochemical analyses on tauopathy mice, FTLD, and AD subjects. We showed that oligomers co-localize with astrocytes, microglia, and HMGB1, a pro-inflammatory cytokine. Additionally, we show that tau oligomers are present in the retina and are associated with inflammatory cells suggesting that the retina may be a valid non-invasive biomarker for brain pathology. These results suggest that there may be a toxic relationship between tau oligomers and inflammation. Therefore, the ability of tau oligomers to spread may initiate a feed-forward cycle in which tau oligomers induce inflammation, leading to neuronal damage, and thus more inflammation. Further mechanistic studies are warranted in order to understand this relationship, which may have critical implications for improving the treatment of tauopathies.
authors.affiliation: Mitchell Center for Neurodegenerative Diseases, University of Texas Medical Branch, Galveston, TX, USA.|Departments of Neurology, Neuroscience and Cell Biology, University of Texas Medical Branch, Galveston, TX, USA.
authors.forename: Ashley N
authors.initials: AN
authors.lastname: Nilson
authors.affiliation: Mitchell Center for Neurodegenerative Diseases, University of Texas Medical Branch, Galveston, TX, USA.|Departments of Neurology, Neuroscience and Cell Biology, University of Texas Medical Branch, Galveston, TX, USA.
authors.forename: Kelsey C
authors.initials: KC
authors.lastname: English
authors.affiliation: Mitchell Center for Neurodegenerative Diseases, University of Texas Medical Branch, Galveston, TX, USA.|Departments of Neurology, Neuroscience and Cell Biology, University of Texas Medical Branch, Galveston, TX, USA.
authors.forename: Julia E
authors.initials: JE
authors.lastname: Gerson
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Texas Medical Branch, Galveston, TX, USA.
authors.forename: T
authors.initials: T
authors.lastname: Barton Whittle
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Texas Medical Branch, Galveston, TX, USA.
authors.forename: C
authors.initials: C
authors.lastname: Nicolas Crain
authors.affiliation: Mitchell Center for Neurodegenerative Diseases, University of Texas Medical Branch, Galveston, TX, USA.|Departments of Neurology, Neuroscience and Cell Biology, University of Texas Medical Branch, Galveston, TX, USA.
authors.forename: Judy
authors.initials: J
authors.lastname: Xue
authors.affiliation: Mitchell Center for Neurodegenerative Diseases, University of Texas Medical Branch, Galveston, TX, USA.|Departments of Neurology, Neuroscience and Cell Biology, University of Texas Medical Branch, Galveston, TX, USA.
authors.forename: Urmi
authors.initials: U
authors.lastname: Sengupta
authors.affiliation: Mitchell Center for Neurodegenerative Diseases, University of Texas Medical Branch, Galveston, TX, USA.|Departments of Neurology, Neuroscience and Cell Biology, University of Texas Medical Branch, Galveston, TX, USA.
authors.forename: Diana L
authors.initials: DL
authors.lastname: Castillo-Carranza
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Texas Medical Branch, Galveston, TX, USA.
authors.forename: Wenbo
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Texas Medical Branch, Galveston, TX, USA.
authors.forename: Praveena
authors.initials: P
authors.lastname: Gupta
authors.affiliation: Mitchell Center for Neurodegenerative Diseases, University of Texas Medical Branch, Galveston, TX, USA.|Departments of Neurology, Neuroscience and Cell Biology, University of Texas Medical Branch, Galveston, TX, USA.
authors.forename: Rakez
authors.initials: R
authors.lastname: Kayed
mesh_terms: D000367:Age Factors; D000818:Animals; D001253:Astrocytes / Q000378:metabolism / Q000473:pathology; D002135:Calcium-Binding Proteins / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004660:Encephalitis / Q000209:etiology* / Q000378:metabolism; D005786:Gene Expression Regulation / Q000235:genetics; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D024243:HMGB1 Protein / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008840:Microfilament Proteins / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D019636:Neurodegenerative Diseases / Q000150:complications* / Q000235:genetics; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D012173:Retinitis / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C491049:Aif1 protein, mouse; D002135:Calcium-Binding Proteins; D016207:Cytokines; D005904:Glial Fibrillary Acidic Protein; D024243:HMGB1 Protein; D008840:Microfilament Proteins; D016875:tau Proteins
keywords: Alzheimer’s disease; frontotemporal lobar dementia; neuroinflammation; oligomer; retinal degeneration; tau protein; tauopathy