Fig. 3: Murine APP does not affect PV interneuron physiology, but mAPP/hAB chimera replicates partial findings of hAPP-induced deficits.

a Pictorial representation of differing amino acids between murine APP and human APP proteins; 26 different amino acids in total, 3 of which are in the amyloid-beta segment of the protein. b Graphical summary of AAV.E2.tdTom and AAV.EF1a.mAPP (or for Ctrl, saline) stereotactic injection in the Lateral Entorhinal Cortex. PV interneurons were fluorescently targeted for whole-cell current clamp recordings. AP firing elicited by square pulse current injections of varying magnitude normalized to cellular capacitance during recording in PV interneurons from Ctrl (left) and mAPP injected (right) L2 LEC at 12 pA/pF. c Group data summary of AP firing frequency in Ctrl and mAPP injected mice. PV interneurons between Ctrl and mAPP injected showed no difference in AP Frequency (Hz) (Ctrl: Max: 122.3 ± 11.11 Hz, mAPP: Max: 120.6 ± 11.50 Hz, p = 0.95). Statistical significance is denoted as *p < 0.05, as determined by Two-way ANOVA with Sidak’s multiple comparison test. d RNAscope quantification for APP copies per PV+ cell with APP injected (mAPP or hAPP) each normalized to their contralateral hemisphere average endogenous murine APP copy per PV+ cell. mAPP injected and hAPP injected mice show similar increases in increased APP expression. copies per PV+ cell (p = 0.84, t = 0.21, df = 9; two-tailed unpaired t-test), data points represent biological replicates; mAPP n = 6, hAPP n = 5. e Pictorial representation of the resultant Chimera protein; murine APP with a humanized amyloid-beta segment. f Graphical summary of AAV.E2.tdTom and AAV.EF1a.mAPP/hAB Chimera (or for Ctrl, saline) stereotactic injection in the Lateral Entorhinal Cortex. PV interneurons were fluorescently targeted for whole-cell current clamp recordings. AP firing elicited by square pulse current injections of varying magnitude normalized to cellular capacitance during recording in PV interneurons from Ctrl (left) and Chimera injected (right) L2 LEC at 12 pA/pF. g Group data summary of AP firing frequency in Ctrl and Chimera injected mice. PV interneurons between Ctrl and mAPP injected showed no difference in AP Frequency (Hz) (Ctrl: Max: 193.6 ± 19.47 Hz, mAPP: Max: 145.4 ± 14.05 Hz, p < 0.0001; for 12 pA p = 0.0378, for 14 pA p = 0.0368, for 16 pA p = 0.0426). Statistical significance is denoted as *p < 0.05, as determined by Two-way ANOVA with Sidak’s multiple comparison test. h Comparison of PV interneuron firing frequencies expressing mAPP, mAPP/hAB Chimera, or hAPP normalized to their dataset controls at 12 pA/pF. Statistical significance is denoted as *p < 0.05, as determined by Ordinary one-way ANOVA with Tukey’s multiple comparisons test. (mAPP vs. Chimera: p = 0.0011, mAPP vs. hAPP: <0.0001, Chimera vs. hAPP: p = 0.0335; df = 35), data points represent technical replicates (cells) normalized to their own group controls, mAPP n = 11, Chimera n = 16, hAPP n = 11. Box plots (mAPP: minimum: 0.6925, 25% percentile: 0.8446, median: 1.065, 75% percentile: 1.420, maximum: 1.541, range: 0.8487; Chimera: minimum: 0.1538, 25% percentile: 0.5879, median: 0.7143, 75% percentile: 0.8571, maximum: 1.033, range: 0.8791; hAPP: minimum: 0.0000, 25% percentile: 0.1022, median: 0.3292, 75% percentile: 0.6360, maximum: 0.9407, range: 0.9407). For all summary graphs, data are expressed as mean ( ± SEM). Source data are provided as a Source Data File.