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Neuronal loss and inflammation preceding fibrillary tau pathology in a rat model with early human-like tauopathy.
Emmerson, Joshua T; Malcolm, Janice C; Do Carmo, Sonia; Nguyen, Phuoc; Breuillaud, Lionel; Martinez-Trujillo, Julio C; Cuello, A Claudio.
Afiliación
  • Emmerson JT; Department of Pharmacology & Therapeutics, McGill University, Montreal H3G 1Y6, Canada.
  • Malcolm JC; Department of Cell Anatomy and Cell Biology, McGill University, Montreal H3A 0C7, Canada.
  • Do Carmo S; Department of Pharmacology & Therapeutics, McGill University, Montreal H3G 1Y6, Canada.
  • Nguyen P; Department of Pharmacology & Therapeutics, McGill University, Montreal H3G 1Y6, Canada.
  • Breuillaud L; Department of Pharmacology & Therapeutics, McGill University, Montreal H3G 1Y6, Canada.
  • Martinez-Trujillo JC; Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Robarts Research Institute and Brain and Mind Institute, University of Western Ontario, ON N6A 5B7, Canada; Lawson Health Research Institute, London, ON N6A 5B7, Canada.
  • Cuello AC; Department of Pharmacology & Therapeutics, McGill University, Montreal H3G 1Y6, Canada; Department of Cell Anatomy and Cell Biology, McGill University, Montreal H3A 0C7, Canada; Visiting Professor, Department of Pharmacology, Oxford University, Oxford, UK, OX1 3QT. Electronic address: claudio.cu
Neurobiol Dis ; 187: 106317, 2023 Oct 15.
Article en En | MEDLINE | ID: mdl-37802153
In tauopathies such as Alzheimer's disease (AD) and frontotemporal dementia (FTD), the microtubule associated protein tau undergoes conformational and posttranslational modifications in a gradual, staged pathological process. While brain atrophy and cognitive decline are well-established in the advanced stages of tauopathy, it is unclear how the early pathological processes manifest prior to extensive neurodegeneration. For these studies we have applied a transgenic rat model of human-like tauopathy in its heterozygous form, named McGill-R955-hTau. The goal of the present study was to investigate whether lifelong accumulation of mutated human tau could reveal the earliest tau pathological processes in a context of advanced aging, and, at stages before the overt aggregated or fibrillary tau deposition. We characterized the phenotype of heterozygous R955-hTau rats at three endpoints, 10, 18 and 24-26 months of age, focusing on markers of cognitive capabilities, progressive tau pathology, neuronal health, neuroinflammation and brain ultrastructural integrity, using immunohistochemistry and electron microscopy. Heterozygous R955-hTau transgenic rats feature a modest, life-long accumulation of mutated human tau that led to tau hyperphosphorylation and produced deficits in learning and memory tasks after 24 months of age. Such impairments coincided with more extensive tau hyperphosphorylation in the brain at residues pThr231 and with evidence of oligomerization. Importantly, aged R955-hTau rats presented evidence of neuroinflammation, detriments to myelin morphology and detectable hippocampal neuronal loss in the absence of overt neurofibrillary lesions and brain atrophy. The slow-progressing tauopathy of R955-hTau rats should allow to better delineate the temporal progression of tau pathological events and therefore to distinguish early indicators of tauopathy as having the capability to induce degenerative events in the aged CNS.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Tauopatías / Enfermedades Neuroinflamatorias Límite: Aged / Animals / Humans Idioma: En Revista: Neurobiol Dis Asunto de la revista: NEUROLOGIA Año: 2023 Tipo del documento: Article País de afiliación: Canadá Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Tauopatías / Enfermedades Neuroinflamatorias Límite: Aged / Animals / Humans Idioma: En Revista: Neurobiol Dis Asunto de la revista: NEUROLOGIA Año: 2023 Tipo del documento: Article País de afiliación: Canadá Pais de publicación: Estados Unidos