Joel, Z;
Izquierdo, P;
Liu, W;
Hall, C;
Roberts, M;
Yap, K;
Nick, A;
... Edwards, F; + view all
(2018)
A TauP301L mouse model of dementia; development of pathology, synaptic transmission, microglial response and cognition throughout life.
BioRxiv: Cold Spring Harbor, NY, USA.
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Abstract
Background: Late stage Alzheimer's disease and other dementias are associated with neurofibrillary tangles and neurodegeneration. Here we describe a mouse (TauD35) carrying human Tau with the P301L mutation that results in Tau hyperphosphorylation and tangles. Previously we have compared gene expression in TauD35 mice to mice which develop plaques but no tangles. A similar comparison of other pathological features throughout disease progression is made here between amyloidβ and Tau mice. Methods: In vitro CA1 patch clamp and field recordings were used to investigate synaptic transmission and plasticity. Plaque load and microglia were investigated with immunohistochemistry. Cognition, locomotor activity and anxiety-related behaviours were assessed with a forced-alternation T-maze, open field and light/dark box. Results: Transgene copy number in TauD35 mice fell into two groups (HighTAU and LowTAU), allowing assessment of dose-dependent effects of overexpression and resulting in tangle load increasing 100-fold for a 2-fold change in protein levels. Tangles were first detected at 8 (HighTAU) or 13 months (LowTAU) but the effects on synaptic transmission and plasticity and behaviour were subtle. However severe neurodegeneration occurred in HighTAU mice at around 17 months preceded by considerable proliferation but little additional activation of microglia. Proliferation only started as neurodegeneration began at 13 months. Similarly to HighTau mice at 13 months of age, LowTAU mice at 24 months of age showed a comparable tangle load and microglial proliferation. However, LowTAU mice showed no neurodegeneration at this stage and considerable microglial activation, stressing the dependence of these effects on overexpression and/or age. Conclusions: Comparison of the effects of amyloidβ and plaques without tangles in a model of preclinical Alzheimer's disease to the effects of tangles without amyloidβ plaques in the late stage model described here may clarify the progressive stages of Alzheimer's disease. While Tau hyperphosphorylation and neurofibrillary tangles are eventually sufficient to cause severe neurodegeneration, initial effects on synaptic transmission and the immune response are subtle. In contrast while even with a heavy plaque load little if any neurodegeneration occurs, considerable effects on synaptic transmission and the immune system result, even before plaques are detectable.
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