BIN1 favors the spreading of Tau Andrea Crotti1,*, Hameetha Rajamohamendsait1, Galina Marsh1, Michael Craft1, Nilsa Silva1, Luke Jandreski1, Stefan Hamann1, Taylor Reynolds1, Andrew Cameron1, Karol Estrada1, Ayla Ergun1, Richard Ransohoff2, Ellen Cahir-McFarland1 1Biogen, 225 Binney St., Cambridge, MA, 02142, USA; 2Third Rock Ventures, Boston *firstname.lastname@example.org
BIN1 represents the most statistically significant susceptibility locus associated to Late Onset Alzheimer's Disease (LOAD), after ApoE. Nevertheless, the mechanisms underlying the contribution of BIN1 to AD pathogenesis are still not understood. BIN1 SNPs are significantly associated with the level of total tau and ptau in the CSF, but not with Ab. Interestingly, the majority of ptau181 has been found in exosomes purified from CSF of individuals affected by Mild AD. Given that exosomes are one possible mechanism through which tau spreads from cell-to-cell, and BIN1-containing extracellular vesicles are released via exosomes-related complex ESCRT-III, we investigated whether BIN1 could affect tau spreading via exosomes secretion. We observed that BIN1 and tau are present in seeding competent exosomes purified from CSF of AD affected individuals. Overexpression of BIN1 increases the release of tau via exosomes in vitro, and exacerbate tau pathology in the hippocampus of tau P301S mice injected with AAV-BIN1 in vivo. Since it has been reported that microglia may spreads tau via exosomes secretion, we investigated whether loss of Bin1 in microglia would affect tau release via exosomes. Preliminary results show that loss of Bin1 in microglia leads to a reduction of tau secreted via exosomes in vitro. These data suggest that BIN1 could contributes to the progression of AD-related tau pathology via exosomes-associated tau secretion.
Authors of the research are Biogen employees. Funding for the research have been provided by Biogen. Human samples had been provided by Nederland Brain Bank.
Credits: None available.
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