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. 2013 Nov 20;8(11):e80834.
doi: 10.1371/journal.pone.0080834. eCollection 2013.

Tau causes synapse loss without disrupting calcium homeostasis in the rTg4510 model of tauopathy

Katherine J Kopeikina  1 , Susanne Wegmann, Rose Pitstick, George A Carlson, Brian J Bacskai, Rebecca A Betensky, Bradley T Hyman, Tara L Spires-Jones
Affiliations

Tau causes synapse loss without disrupting calcium homeostasis in the rTg4510 model of tauopathy

Katherine J Kopeikina et al. PLoS One. .

Abstract

Neurofibrillary tangles (NFTs) of tau are one of the defining hallmarks of Alzheimer's disease (AD), and are closely associated with neuronal degeneration. Although it has been suggested that calcium dysregulation is important to AD pathogenesis, few studies have probed the link between calcium homeostasis, synapse loss and pathological changes in tau. Here we test the hypothesis that pathological changes in tau are associated with changes in calcium by utilizing in vivo calcium imaging in adult rTg4510 mice that exhibit severe tau pathology due to over-expression of human mutant P301L tau. We observe prominent dendritic spine loss without disruptions in calcium homeostasis, indicating that tangles do not disrupt this fundamental feature of neuronal health, and that tau likely induces spine loss in a calcium-independent manner.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. Yellow cameleon imaging in rTg4510 and control mice.
In vivo multiphoton imaging of somatosensory cortex neurons expressing the ratiometric calcium indicator YC3.6 (A) demonstrates that the indicator fills both dendrites (B, blue arrow heads) and dendritic spines (B, yellow arrow heads). Calcium concentration images from control (C) and rTg4510 (D) mice were calculated from YC ratio (YFP/CFP) images and color-coded according to the color gradient shown in the middle. Scale bars (B, C, D) represent 10 μm.
Figure 2
Figure 2. Calcium concentrations in dendrites and spines are not disrupted by tau over-expression.
Average YC ratios (YFP/CFP) and calcium concentrations recorded from dendrites and dendritic spines in control and rTg4510 mice (A). Distributions of YC ratios in dendrites and dendritic spines from control (B, C) and rTg4510 mice (E, F) show no significant difference between control and rTg4510 mice. The dashed vertical lines indicate calcium overload thresholds at the 95th percentile of the control mice data, determined for dendrites and spines separately. Data are shown as mean ± standard deviation.
Figure 3
Figure 3. Spine loss in rTg4510 mice is independent of calcium dysregulation.
High-resolution in vivo images of dendrites and spines from control (A) and rTg4510 (B) show substantial loss of spines in rTg4510 mice. For better visualization, the image background was removed and the contrast adjusted. Analysis of dendritic spine densities was performed on raw images. The average dendritic spine density (C) was significantly decreased in rTg4510 mice when compared to controls (*, p < 0.05). Spine density in rTg4510 mice did not significantly correlate with YC ratios in the parental dendrite (D). Scale bars (A, B) represent 5 μm.
See this image and copyright information in PMC

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