Journal
NEUROBIOLOGY OF DISEASE
Volume 127, Issue -, Pages 323-338Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.nbd.2019.03.018
Keywords
Alzheimer's disease; Tauopathy; Rat model; FTDP-17T; Inflammation; Neurodegeneration; Gliosis; Neuronal loss
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Funding
- Frosst family
- Merck Canada
- Canadian Institute of Health Research [201603PJT-364544]
- Rotary Foundation Global Grant Scholarship
- Doctoral Training Fellowship from the Fonds de recherche du Quebec - Sante
- UK Medical Research Council [MC_U105184291]
- MRC [MC_U105184291] Funding Source: UKRI
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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.
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