Loss of Bin1 expression affects neuronal survival in vivo in mice expressing tau P301S
Andrea Crotti1,*, Hameetha Rajamohamendsait1, Galina Marsh1, Michael Craft1, Nilsa Silva1, Luke Jandreski1, Stefan Hamann1, Taylor Reynolds1, Andrew Cameron1, Karol Estrada1, Ayla Ergun1, Ellen Cahir-McFarland1 1Biogen, 225 Binney St., Cambridge, MA, 02142, USA *email@example.com
BIN1 has been identified as the most important risk locus for Late Onset Alzheimer's Disease (LOAD), after ApoE. BIN1-associated SNPs correlate with tau deposition as well as with hippocampal atrophy. Furthermore, while the total amount of BIN1 mRNA increases, the level of neuronal-specific BIN1 isoform 1 protein is decreased in sporadic AD cases and this decrease parallels to neuronal loss. To understand whether the loss of BIN1 in conjunction to tau deposition is causative of neuronal loss, we knocked-down endogenous murine Bin1 via stereotaxic injection of AAV-Bin1 shRNA in the hippocampus of mice expressing tau P301S (PS19). We observed a statistically significant reduction in the number of neurons in the hippocampus of mice injected with AAV-Bin1 shRNA in comparison with mice injected with AAV control. To investigate whether the neuronal loss is due to deletion of Bin1 in neurons in presence or in absence of tau P301S, we bred Bin1fl/fl mice with mice expressing Cre under the neuronal promoter of Thy1, and subsequently with PS19. We observed that mice lacking Bin1 exclusively in neurons and expressing tau P301S die earlier, and show increased freezing time in fear conditioning experiments in comparison to PS19 expressing neuronal Bin1. Furthermore, we observed that mice lacking Bin1 in neurons in absence of tau P301S showed a decrease in the number of CA1 neurons in the hippocampus as well as increased susceptibility to pharmacologically-induced seizure. Taken together, our data suggest that the effect of BIN1 on Alzheimer's Disease risk could be partially due to a cell autonomous role of neuronal Bin1, eventually exacerbated by the presence of mutant tau. Further studies are currently ongoing to understand the mechanisms underlying these effects.
Authors of the research are Biogen employees. Funding for the research have been provided by Biogen.
Credits: None available.
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