Fig. 1: The injection of pathological tau seeds derived from patients triggers inflammatory responses and neuronal cell loss in mice.
From: Alzheimer’s Tau seeds-induced pathology enhances hippocampal extracellular diffusion
A Tau seeds were purified from the brain of Alzheimer’s disease patients at Braak stage VI. B A filtration binding assay (dot blot) pl recombinant tau protein (ranging from 15 to 0.08 µg, 1). This method also permitted the detection of P(Ser202, Thr205)Tau in the extracts (4, 5 duplicates). The presence of both 3 R and 4 R isoforms was confirmed by slot blot (6, 7). C Stereotactic injection of tau extracts, or PBS was performed in mouse hippocampus10. Four months post-injection, animals were terminated, and their brains were used either for immunostaining analysis (n = 5 mice PBS, n = 9 mice Tau) or QDs SPT. We restrained our analysis to the granular area and proximal CA3 regions. D NeuN labeling of ipsi and contralateral tau-injected hippocampi. Auto-fluorescent (AF) signal appears in the GFP channel stretching from the granular/hilar region, extending towards the Interventricular Foramen and third ventricle. E Quantification of NeuN signal integrated density (Area * Mean Intensity) reveals neuronal death and/or structural atrophy: (mean ± SEM) Hilus: PBS: 1.01 ± 0.03, Tau 0.782 ± 0.06 Mann Whitney test p-value = 0.0102; Granular cells: PBS: 0.997 ± 0.043, Tau 0.888 ± 0.09 Mann Whitney test p-value = 0.24; CA3 py: PBS: 1.10 ± 0.092, Tau 0.67 ± 0.07 Mann Whitney test p-value = 0.007; CA3or: PBS: 1.09 ± 0.082, Tau 0.996 ± 0.077 Mann Whitney test p-value = 0.44). F AF objects are surrounded by the lysosomal marker LAMP-1 and are usually in direct contact, sometimes swollen with (G) IBA-1-positive activated microglia. H 63x confocal micrographs of granular (top) and CA3 pyramidal areas (bottom). The model presents AT-8 puncta exclusively in the Tau-injected mice (AT-8% Area, Mean ± SEM: PBS: 0.012 ± 0.0016, Tau = 0.092 ± 0.025, Kruskal-Wallis test p-value = 0.0010). I, J There is a microglial hyper-activation in our zones under study measured by IBA-1 density (%surface IBA-1 ipsi/contra (mean ± SEM) Hilus: PBS: 118.5 ± 14.8, Tau 185.1 ± 19.7 Mann Whitney test p-value = 0.042; Granular cells: PBS: 118.0 ± 8.86, Tau 160.1 ± 29.3 Mann Whitney test p-value = 0.63; CA3 py: PBS: 145.0 ± 32.8, Tau 205 ± 14.5 Mann Whitney test p-value = 0.12; CA3 or: PBS: 95.3 ± 9.1, Tau 146 ± 5.1 Mann Whitney test p-value = 0.0005). K qPCR on tissue homogenates extracted from CA3-DG area (n = 3 mice). We found significant increases in inflammation and apoptosis genes (Il-6 p-value = 0.038, Casp3 p-value = 0.04). Error bars represent mean ± SD. Created in BioRender. Bezard, E. (2025) https://BioRender.com/b68b484.
