Journal
NEUROBIOLOGY OF AGING
Volume 33, Issue 3, Pages -Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.neurobiolaging.2011.02.014
Keywords
Tau; Knockin mouse; P301L mutation; FTDP-17T; Axonal transport; Mitochondria
Categories
Funding
- UK Medical Research Council
- Biotechnology and Biological Sciences Research Council
- Belgian Federal Science Policy Office (BELSPO) [P6/43]
- Diane Program (Wallon region)
- Alzheimers Research UK [ART-EG2004A-1] Funding Source: researchfish
- Medical Research Council [G0300408] Funding Source: researchfish
- MRC [G0300408] Funding Source: UKRI
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Tauopathies are characterized by hyperphosphorylation of the microtubule-associated protein tau and its accumulation into fibrillar aggregates. Toxic effects of aggregated tau and/or dysfunction of soluble tau could both contribute to neural defects in these neurodegenerative diseases. We have generated a novel knockin mouse model of an inherited tauopathy, frontotemporal dementia with parkinsonism linked to tau mutations on chromosome 17 (FTDP-17T). We incorporated a single mutation, homologous to the common FTDP-17T P301L mutation, directly into the endogenous mouse gene, mimicking the human disease situation. These mice express P301L-equivalent mutant tau at normal physiological levels from the knockin allele. Importantly, in contrast to existing transgenic mouse models that overexpress human P301L mutant tau, no overt tau pathology developed during the normal lifespan of the knockin mice. In fact, overall phosphorylation of tau was reduced, perhaps due to reduced microtubule binding. However, homozygous knockin mice did display intriguing age-dependent changes in axonal transport of mitochondria, and increased spontaneous locomotor activity in old age. These could represent early consequences of the tau dysfunction that eventually precipitates pathogenesis in humans. (C) 2012 Elsevier Inc. All rights reserved.
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