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Fig. 9 | Acta Neuropathologica Communications

Fig. 9

From: Resistance and resilience to Alzheimer’s disease pathology are associated with reduced cortical pTau and absence of limbic-predominant age-related TDP-43 encephalopathy in a community-based cohort

Fig. 9

hTau and hTDP-43 synergize in vivo to drive neurotoxicity and protein accumulation. a, b Pan-neuronal expression of human TDP-43 (hTDP-43) is synthetic lethal with human Tau (hTau) in C. elegans transgenic models. Progeny from animals homozygous for hTau tg (+/+) but heterozygous for either GFP Tg or hTDP-43 tg (+/−) were picked blind and then scored for GFP Tg or hTDP-43 tg genotype. Expected Mendelian ratios for assortment of a single genetic element are 25% (+/+), 50% (+/−), and 25% (−/−). Ratios of progeny from animals heterozygous for GFP Tg are not significantly different from Mendelian ratios (p = 0.502, Chi square analysis). Ratios of progeny from animals heterozygous for hTDP-43 tg are significantly different from Mendelian ratios (p < 0.0001). N = 563, GFP Tg. N = 561, hTDP-43 tg. c Developmentally synchronized L4 larvae of hTau tg (+/+); TDP-43 (+/+) double homozygotes move significantly less than hTau tg (+/+) or hTDP-43 tg (+/+) alone (****p < 0.0005). Statistical significance was determined using one-way ANOVA with Tukey’s multiple-comparison test. d Co-expression of hTau and hTDP-43 promotes accumulation and pathological phosphorylation of both proteins in vivo. Developmentally synchronized day 1 adult C. elegans were harvested and tested by immunoblot for total tau, phosphorylated tau (AT180), total TDP-43, phosphorylated TDP-43 (phospho-S409/410) and tubulin (load control). Immunoblot shown is representative of three independent replicate experiments

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