Fig. 3

The presence of LATE-NC is associated with p-tau seeding severity in TDP-43^A315T mice. a Transgenic TDP-43^A315T mice were stereotactically injected in the hippocampus at 1 year of age with human brain sarkosyl-insoluble homogenates of 1 aged control, n = 9; 1 AD(LATE-NC-), n = 10; 1 AD(LATE-NC+), n = 9 and 1 FTLD-TDP case, n = 7 or with PBS, n = 7. Animals were sacrificed 4 months post-injection and their brains were histologically evaluated: the spread of p-tau seeding was evaluated in 12 hippocampal sections covering the whole hippocampus from anterior to posterior hippocampus (hAP score). Among these, a “hotspot” section was selected and the severity of p-tau aggregation was also quantified. b P-tau202/204 immunostaining of experimental groups displaying the central white matter band. Extracellular, neuropil p-tau seeds are visible in AD(LATE-NC-) and AD(LATE-NC+) -injected mice, being more pronounced in AD(LATE-NC+)-injected mice (arrows); scale bars = 500µm. c Quantification of the hAP score for each experimental groups; average percentages of positive sections (out of 12) are displayed. Animals injected with AD(LATE-NC-) and AD(LATE-NC+) extracts showed a significantly increased hAP score in the ipsilateral and contralateral compared to control-injected animals, pointing to a similar spread of p-tau seeds among both groups. Importantly, AD(LATE-NC+)-injected animals showed an increased number of p-tau202/205-positive particles (i.e.: seeding severity) compared to the AD(LATE-NC-) and control group, in the (d) ipsilateral as well as in the (e) contralateral. Multiple linear regressions (least squares) were performed to compare the hAP score and the number of p-tau particles among groups. The FTLD-TDP and PBS groups were excluded from both analyses as they showed no p-tau seeding