Neuropathological changes and cognitive deficits in rats transgenic for human mutant tau recapitulate human tauopathy
| Autor: | Lindsay A. Welikovitch, A. Claudio Cuello, Sonia Do Carmo, Hélène Hall, Lionel Breuillaud, Jennifer A. Macdonald, Janice C. Malcolm, Michel Goedert |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
MRI Magnetic resonance imaging Morris water navigation task EM Electron microscopy Frontotemporal dementia and parkinsonism linked to chromosome 17 FTDP-17T 0302 clinical medicine Gliosis PFA Paraformaldehyde Inclusion Bodies CNS Central nervous system Neurodegeneration Brain EDTA Ethylenediaminetetraacetic acid Alzheimer's disease EGTA Ethylene glycol-bis(β-aminoethyl ether)-N N N′ N′-tetraacetic acid TBS Tris buffered saline CaMKIIα Calcium/calmodulin-dependent protein kinase II alpha subunit Tauopathy medicine.anatomical_structure Tauopathies Neurology NFT Neurofibrillary tangle Rat model Neuronal loss AD Alzheimer's disease Iba1 Ionized calcium-binding adapter molecule 1 Rats Transgenic medicine.symptom HRP Horseradish peroxidase NOL Novel Object Location FTDP-17T Frontotemporal dementia and parkinsonism linked to chromosome 17 caused by MAPT mutations Central nervous system Tau protein PBS Phosphate buffered saline tau Proteins Biology Article lcsh:RC321-571 03 medical and health sciences BSA Bovine serum albumin Atrophy PMSF Phenylmethylsulfonyl fluoride medicine Animals Cognitive Dysfunction lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry Inflammation GFAP Glial Acidic Fibrillary Protein medicine.disease Rats Disease Models Animal MAPT Microtubule-associated protein tau NOR Novel Object Recognition 030104 developmental biology biology.protein PCR Polymerase chain reaction Neuroscience 030217 neurology & neurosurgery |
| Zdroj: | Neurobiology of Disease Neurobiology of Disease, Vol 127, Iss, Pp 323-338 (2019) |
| ISSN: | 0969-9961 |
| DOI: | 10.1016/j.nbd.2019.03.018 |
| Popis: | The assembly of tau protein into abnormal filaments and brain cell degeneration are characteristic of a number of human neurodegenerative diseases, including Alzheimer's disease and frontotemporal dementia and parkinsonism linked to chromosome 17. Several murine models have been generated to better understand the mechanisms contributing to tau assembly and neurodegeneration. Taking advantage of the more elaborate central nervous system and higher cognitive abilities of the rat, we generated a model expressing the longest human tau isoform (2N4R) with the P301S mutation. This transgenic rat line, R962-hTau, exhibits the main features of human tauopathies, such as: age-dependent increase in inclusions comprised of aggregated-tau, neuronal loss, global neurodegeneration as reflected by brain atrophy and ventricular dilation, alterations in astrocytic and microglial morphology, and myelin loss. In addition, substantial deficits across multiple memory and learning paradigms, including novel object recognition, fear conditioning and Morris water maze tasks, were observed at the time of advanced tauopathy. These results support the concept that progressive tauopathy correlates with brain atrophy and cognitive impairment. Highlights • A transgenic rat model expressing the full length human tau with the P301S mutation. • Progressive human-like tau brain pathology with recruitment of endogenous rodent tau. • Pathology-induced gliosis, myelin breakdown, neuronal loss and ventricular dilation. • Widespread behavioural deficits occur at end-stage tau pathology. |
| Databáze: | OpenAIRE |
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