Fig. 7: hTau co-expression with hAPP quells hyperexcitability but increases pathological tau.

a Graphical summary of AAV.EF1a.hAPP, AAV.EF1a.MAPT (hTau), or co-injected AAV.EF1a.hAPP with AAV.EF1a.MAPT stereotactic injection in the Lateral Entorhinal Cortex. Excitatory cells were targeted for whole-cell voltage-clamp recordings. b Spontaneous events obtained by holding cell voltage at −70 mV (excitatory post-synaptic currents, EPSCs [top]) and 0 mV (inhibitory post-synaptic currents, IPSCs [bottom]), interleaved. Quantified averages of event frequency are displayed for each cell normalized to Ctrl values as a ratio of EPSC Frequency to IPSC frequency and compared between hAPP injected (magenta), hTau injected (gray) and hAPP + hTau co-injected (pink) conditions. L2 LEC injected with hAPP showed a significantly elevated E:I ratio compared to hTau injected (p = 0.0136, df=20). hAPP and hTau co-injected E:I ratio was not significantly different from hAPP injected (p = 0.3323, df = 20) or hTau injected (p = 0.2175, df = 20). For all summary graphs, data are expressed as mean ( ± SEM), data points represent technical replicates (cells). Statistical significance is denoted as *p < 0.05, as determined by an Ordinary one-way ANOVA with Multiple comparisons. Box plot data: hAPP: minimum: 1.292, 25% percentile: 1.315, median: 1.539, 75% percentile: 2.317, maximum: 2.765, range: 1.473; hTau: minimum: 0.6859, 25% percentile: 0.7222, median: 0.8825, 75% percentile: 1.318, maximum: 1.600, range: 0.9138; hAPP+ hTau: minimum: 0.8832, 25% percentile: 1.062, median: 1.410, 75% percentile: 1.913, maximum: 1.989, range: 1.105. IHC representative images at 60x magnification for hTau (top) or hAPP+hTau (bottom) injected mice (for Ctrl or hAPP injected, see Supplementary Fig. 15) with staining for either AH36 (c) or T22 (e). d hAPP, hTau, and hAPP+hTau were analyzed for AH36 brightness in the first 100 um of every slice. AH36 brightness was normalized to CaMKII.eYFP brightness to control for any potential variability in viral expression. All groups were then normalized to the Ctrl injected condition. hAPP+hTau showed the highest level of AH36 brightness, although it was not significant over hAPP (p = 0.1267) or hTau (p = 0.4900) (df = 8, One-Way ANOVA with Multiple Comparisons). hAPP and hTau were also not significantly different (p = 0.5328). Box plot data: hAPP: minimum: 0.3056, 25% percentile: 0.3258, median: 0.9949, 75% percentile: 1.986, maximum: 2.113, range: 1.807; hTau: minimum: 0.9517, 25% percentile: 1.112, median: 1.673, 75% percentile: 2.038, maximum: 2.133, range: 1.182; hAPP+hTau: minimum: 1.916, 25% percentile: 1.916, median: 2.193, 75% percentile: 2.469, maximum: 2.469, range: 0.5531. f hAPP, hTau, and hAPP+hTau were analyzed for T22 brightness in the first 100 um of every slice. T22 brightness was normalized to CaMKII.eYFP brightness to control for any potential variability in viral expression. All groups were then normalized to the Ctrl injected condition. hAPP+hTau showed a significantly higher level of T22 brightness, above both hAPP (p = 0.0350) and hTau (p = 0.0.0389) (df = 8, One-Way ANOVA with Multiple Comparisons). hAPP and hTau were not significantly different (p = 0.9526). Box plot data: hAPP: minimum: 0.5981, 25% percentile: 0.5981, median: 1.048, 75% percentile: 1.206, maximum: 1.206, range: 0.6079; hTau: minimum: 0.4814, 25% percentile: 0.5575, median: 0.9968, 75% percentile: 1.699, maximum: 1.863, range: 1.382; hAPP+hTau: minimum: 1.776, 25% percentile: 1.782, median: 2.164, 75% percentile: 3.071, maximum: 3.252, range: 1.476. Source data are provided as a Source Data File.