Fig. 2: APOE deficiency inhibited amyloid-facilitated tau pathology in hippocampus and frontal cortex in an ATN model.

A Representative images of the hippocampus and frontal cortex of F ⁺T ⁺ ApoE WT and F ⁺T ⁺ ApoE KO mice stained with AT8 and W02 antibody, respectively staining p-tau pathology (top and bottom row), Aβ load (second row), and overlay (third row), showing a pronounced decrease in AT8 stained area in F ⁺T ⁺ ApoE KO compared to F ⁺T ⁺ ApoE WT mice. Bottom row shows higher magnification of p-tau pathology. Scalebar represents 500 µm (top rows) and 125 µm (bottom row). B Quantitative analysis of AT8 stained area in the hippocampus (left) and frontal cortex (right) of F ⁺T ⁺ ApoE WT (n = 17) and F ⁺T ⁺ ApoE KO (n = 16) mice, and of the ratio of AT8 stained area over W02 stained area in the hippocampus (left) and frontal cortex (right) of F ⁺T ⁺ ApoE WT (n = 17) and F ⁺T ⁺ ApoE KO (n = 16) mice. Following normality testing unpaired student t-test was used. Results were presented as mean ± standard error (SEM). *p <  0.05, **p <  0.01, ****p <  0.0001. C Linear regression analysis between W02 stained area and AT8 stained area in frontal cortex and hippocampus, respectively, reveals a more than 5 times steeper slope in F ⁺T ⁺ ApoE WT compared to F ⁺T ⁺ ApoE KO brains (1/slope is respectively 9.1 in F ⁺T ⁺ ApoE WT (p < 0.001) vs 59.8 in F ⁺T ⁺ ApoE KO (p = 0.003) in hippocampus, and 25.9 in F ⁺T ⁺ ApoE WT (p = 0.0006) vs 144.6 in F ⁺T ⁺ ApoE KO (p = 0.0066) in frontal cortex (F ⁺T ⁺ ApoE WT; n = 17; F ⁺T ⁺ ApoE KO; n = 16). D Schematic overview of Homogenous Time Resolved Fluorescence (HTRF) assay to detect tau aggregates (left). Quantitative analysis of tau aggregation using HTRF assay of homogenates of F ⁺T ⁺ ApoE WT (n = 17) and F ⁺T ⁺ ApoE KO (n = 16) mice (middle). Quantitative analysis of sarkosyl insoluble tau (using AT8 staining p-tau ^{S202, T205}), in sarkosyl insoluble fraction of homogenates of F ⁺T ⁺ ApoE WT (n = 17) and F ⁺T ⁺ ApoE KO (n = 16) mice. Following normality testing Mann-Whitney test was used. Results were presented as mean ± standard error (SEM). **p < 0.01, ***p < 0.001 (right). Detailed analysis of p-tau and total tau in sarkosyl insoluble fractions and total homogenates is presented in Fig. S3. E Representative images of Gallyas silver staining in the CA1 region of the hippocampus (top) and zoom in of the neuronal layer (bottom) of F ⁺T ⁺ ApoE WT and F ⁺T ⁺ ApoE KO mice, showing less neurofibrillary tangles (NFTs) in APOE deficient mice. Detailed analysis of NFT staining (Gallyas silver and pFTAA) is presented in Fig. S3. Scalebar represents 100 µm (top) and 30 µm (bottom). WB-SI western blot – sarkosyl insoluble.