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. 2016 Dec;44(12):3056-3066.
doi: 10.1111/ejn.13442. Epub 2016 Nov 12.

Human tau increases amyloid β plaque size but not amyloid β-mediated synapse loss in a novel mouse model of Alzheimer's disease

Rosemary J Jackson  1 , Nikita Rudinskiy  2 , Abigail G Herrmann  1 , Shaun Croft  1 , JeeSoo Monica Kim  1 , Veselina Petrova  1 , Juan Jose Ramos-Rodriguez  3 , Rose Pitstick  4 , Susanne Wegmann  2 , Monica Garcia-Alloza  3 , George A Carlson  4 , Bradley T Hyman  2 , Tara L Spires-Jones  1
Affiliations

Human tau increases amyloid β plaque size but not amyloid β-mediated synapse loss in a novel mouse model of Alzheimer's disease

Rosemary J Jackson et al. Eur J Neurosci. 2016 Dec.

Abstract

Alzheimer's disease is characterized by the presence of aggregates of amyloid beta (Aβ) in senile plaques and tau in neurofibrillary tangles, as well as marked neuron and synapse loss. Of these pathological changes, synapse loss correlates most strongly with cognitive decline. Synapse loss occurs prominently around plaques due to accumulations of oligomeric Aβ. Recent evidence suggests that tau may also play a role in synapse loss but the interactions of Aβ and tau in synapse loss remain to be determined. In this study, we generated a novel transgenic mouse line, the APP/PS1/rTg21221 line, by crossing APP/PS1 mice, which develop Aβ-plaques and synapse loss, with rTg21221 mice, which overexpress wild-type human tau. When compared to the APP/PS1 mice without human tau, the cross-sectional area of ThioS+ dense core plaques was increased by ~50%. Along with increased plaque size, we observed an increase in plaque-associated dystrophic neurites containing misfolded tau, but there was no exacerbation of neurite curvature or local neuron loss around plaques. Array tomography analysis similarly revealed no worsening of synapse loss around plaques, and no change in the accumulation of Aβ at synapses. Together, these results indicate that adding human wild-type tau exacerbates plaque pathology and neurite deformation but does not exacerbate plaque-associated synapse loss.

Keywords: Alzheimer; amyloid beta; plaque; synapse; tau.

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Figures

Figure 1
Figure 1
Overexpression of human tau increases the cross‐sectional area of ThioS‐positive plaques but not the overall plaque burden. Representative images of dense Aβ‐plaques (ThioS, yellow) and total Aβ (AW7, red) in brain sections were used to measure plaque characteristics (A). Higher resolution images demonstrate the halo of soluble Aβ (white arrows) surrounding dense plaques in APP/PS1/rTg21221 mice and APP/PS1 mice (B). The mean cross‐sectional area of individual ThioS‐positive plaques increased in APP/PS1/rTg21221 compared to APP/PS1 mice (*t‐test, df = 6, P = 0.03) (C). ELISA on crude brain homogenates showed a significant increase (*t‐test df = 8.673, P = 0.023) in the amount of Aβ42 in APP/PS1/rTg21221 mice (D). The percentage area of cortex occupied by plaques (plaque burden) was unchanged (E) as was the thickness of the soluble Aβ halo around dense plaques (F). APP/PS1/rTg21221 n = 5, APP/PS1n = 3, scale bars represent 500 μm in (A) and 20 μm in (B). [Colour figure can be viewed at wileyonlinelibrary.com].
Figure 2
Figure 2
Overexpressing human tau does not affect plaque‐associated neuron loss and astrogliosis in APP/PS1 mice. Representative images of neurons (red, Neurotrace stained; A,B) and GFAP‐positive astroglia (red; C,D) and ThioS‐positive plaques (green) in APP/PS1 (A,C) and APP/PS1/rTg21221 (B,D) mice. Neurons were counted in a 30 × 30 μm box for areas near (< 30 μm) and far (> 100 μm) from plaques and as expected there was a decrease in neuronal density in the immediate vicinity of plaques (*two‐way anova F 1,12 = 6.852, p = 0.022). No difference was seen between genotypes (E). GFAP‐positive astrocytes counted in a radius of 30 μm around ThioS‐positive plaques showed no difference either (F). APP/PS1/rTg21221 n = 5, APP/PS1n = 3, scale bar is 30 μm. [Colour figure can be viewed at wileyonlinelibrary.com].
Figure 3
Figure 3
Overexpression of human tau exacerbates plaque‐associated dystrophic neurites but does not affect neurite curvature. Staining of cortical sections neurites (smi312, red), misfolded tau (Alz50, blue), and plaques (ThioS, green) shows the accumulation of tau‐positive dystrophic neurites and the abnormal curvature of neurites near plaques in both APP/PS1 and APP/PS1/rTg21221 mice (A). Neurite curvature was measured by dividing the length (solid line) by the end‐to‐end distance (dotted line) of each neurite segment (B). Quantification reveals an increase in Alz50‐positive dystrophic neurites around plaques in APP/PS1/rTg21221 mice (C) (*t‐test df = 0.047, P = 0.047), whereas the neurite curvature does not change in presence of human tau (D). APP/PS1/rTg21221 n = 5, APP/PS1 n = 3, scale bars are 10 μm (A) and 3 μm (B). [Colour figure can be viewed at wileyonlinelibrary.com].
Figure 4
Figure 4
Overexpression of human tau does not cause tangle formation or increase tau hyperphosphorylation. PHF1 positive tau accumulates in neuropil threads in APP/PS1/rTg21221 mice (A) and in dystrophic neurites in both APP/PS1/rTg21221 (B) and APP/PS1 mice (C). A western blot of crude homogenate from the cortex of a mouse (5 μg protein) was probed for PHF1 (D) and GAPDH (E) as a loading control. The PHF1 bands between 55–65 kDa were quantified and the overexpression of human tau did not change the overall levels of PHF1 (F). APP/PS1/rTg21221 n = 6, APP/PS1n = 3, rTg21221 n = 4 Scale bar 5 μm. [Colour figure can be viewed at wileyonlinelibrary.com].
Figure 5
Figure 5
Overexpression of human tau does not increase synapse loss in APP/PS1 mice. To investigate synapse loss, array tomography ribbons from APP/PS1 (n = 6) and APP/PS1/rTg21221 mice (n = 5) were stained for oligomeric Aβ (oAβ; 1C22), human tau (Tau13), post‐synapses (PSD95), and pre‐synapses (synapsin‐1) (A). There was synapse loss in both genotypes within 20 μm of plaques (*PSD data effect of plaque distance F 1,21 = 8.4, P = 0.01; synapsin data *F 1.21 = 16.6, P = 0.001). There is no exacerbation of synapse loss with expression of human tau of either post‐synaptic terminals (B) or pre‐synaptic terminals (C) (two‐way anova effect of genotype F < 0.5, P > 0.05). Scale bar is 10 μm. [Colour figure can be viewed at wileyonlinelibrary.com].
Figure 6
Figure 6
Overexpression of human tau does not affect the localization of Aβ at synapses. Analysis of the co‐localization of Aβ labeled with 1C22 and PSD95 or synapsin‐1 (A) show that Aβ presence at pre‐synapses (B) or post‐synapses (C) does not change when human tau is overexpressed in APP/PS1/rTg21221 mice (two‐way anova effect of genotype F < 0.3, P > 0.05). In both pre and post synapses, there is a significantly higher percentage of synapses containing Aβ near plaques vs. far from plaques (PSD data effect of plaque distance *F 1,21 = 363.6, P = 2.19 × 10−13; synapsin data *F 1,21 = 13.3, P = 0.002). APP/PS1/rTg21221 n = 5, APP/PS1 n = 6, scale bar is 10 μm, scale bar for insert is 2 μm. [Colour figure can be viewed at wileyonlinelibrary.com].
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