Fig. 10: Enteric neurons are vulnerable to pathogenic tau and lead to significant enteric neuron loss in tau SPAM mice.

a Immunoblot of lysates from different organs as indicated above each lane with antibody CP27 comparing expression in tau SPAM mice and nTg mice show that intestinal expression is very low relative to brain and spinal cord expression levels. 10 μg of protein was loaded per lane. Longer exposure of membrane (below) with only the lanes, including stomach, small intestines, large intestines, spleen, and muscle shows that most of the tau is shifted to relatively higher molecular mass band corresponding to hyperphosphorylated tau. The relative molecular mass markers are shown on the left. b CP27 immunostaining of duodenum, small intestines, and large intestines shows that human tau is more highly expressed in the large intestines. Scale bar = 50 μm for main image and 1 mm for inset. c Tau phosphorylation at Thr205 labeled with antibody 7F2 and (d) at Thr231 labeled with antibody AT180 is found primarily in large intestines of tau SPAM mice and not in nTg mice. e Increased PHF1 staining (against tau phosphorylated Ser396/Ser404) is found throughout the intestinal tract, particularly the large intestines of tau SPAM mice. f Random intestinal slides were sampled throughout the intestinal tract and stained with H&E for estimation of total enteric neurons. At 2 months, there was no statistically significant difference in enteric neuron density between tau SPAM mice and nTg mice (two-tailed t-test, t = 0.8162, df = 112, p = 0.4161) for N = 73 sections for tau SPAM mice and N = 41 sections for nTg mice. ns not statistically significant. g At 4 months, there was no statistically significant difference in enteric neuron density between tau SPAM mice and nTg mice (two-tailed t-test, t = 1.976, df = 127, p = 0.0503) for N = 76 sections in tau SPAM mice and N = 53 sections in nTg mice. ns not statistically significant. h At 6 months, tau SPAM mice had significant neuronal loss (~55% loss of neurons) compared with nTg mice (two-tailed t-test, t = 9.172, df = 195, p < 0.0001) for N = 115 sections in tau SPAM mice and N = 82 sections in nTg mice. Error bars represent standard errors of the mean. ****p < 0.0001.