Fig. 1

Microbial TLR2 agonist cross the blood-brain barrier and induce neurodegeneration after systemic delivery. a Zymosan or lipoteichoic acid were repeatedly injected intraperitoneally to naïve animals or to animals that have been implanted with an ICV pump continuously administering the TLR2 antagonist CU-CPT22. Mice were sacrificed at day 14 to assess neuronal loss. b Following 3 intraperitoneal injections of zymosan or lipoteichoic acid there was significant more loss in cortical neuronal counts in 5xFAD than in wt mice. ICV administration of TLR2 antagonist, CU-CPT22 abolished zymosan-induced neuronal loss. Dashed line represents the baseline NeuN count of untreated wt (blue) and 5xFAD (orange) mice. *Compared with untreated mice. c In wt mice that received intraperitoneal injections of zymosan, followed by intravenous injection of Biocytin-TMR, the BBB tracer was found exclusively within CD31+ blood vessels. d In 5xFAD, zymosan-injected mice Biocytin-TMR crossed the BBB effectively and accumulated in parenchymal brain cells. e–g In 5xFAD mice, pretreated with three intraperitoneal zymosan injections, a fourth injection of fluorescent-labeled zymosan resulted in multiple fluorescent foci in the brain parenchyma (enlarged f inserted in e). Arrowheads show a fluorescent zymosan particle associated with CD31+ blood vessels, arrows show a fluorescent zymosan particle that exited the blood vessel. 3-D confocal images confirmed the exiting of labeled zymosan from CD31+ blood vessels into the brain parenchyma (g)