Cell-autonomous and non-cell autonomous effects of neuronal BIN1 loss in vivo.

BIN1 is the most important risk locus for Late Onset Alzheimer's Disease (LOAD), after ApoE. BIN1 AD-associated SNPs correlate with Tau deposition as well as with brain atrophy. Furthermore, the level of neuronal-specific BIN1 isoform 1 protein is decreased in sporadic AD cases in parallel with neuronal loss, despite an overall increase in BIN1 total mRNA. To address the relationship between reduction of BIN1 and neuronal cell loss in the context of Tau pathology, 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 neuronal loss is due to deletion of Bin1 selectively in neurons in presence Tau P301S, we bred Bin1flox/flox with Thy1-Cre and subsequently with PS19 mice. Mice lacking neuronal Bin1 and expressing Tau P301S showed increased mortality, without increased neuropathology, when compared to neuronal Bin1 and Tau P301S-expressing mice. The loss of Bin1 isoform 1 resulted in reduced excitability in primary neurons in vitro, reduced neuronal c-fos expression as well as in altered microglia transcriptome in vivo. Taken together, our data suggest that the contribution of genetic variation in BIN1 locus to AD risk could result from a cell-autonomous reduction of neuronal excitability due to Bin1 decrease, exacerbated by the presence of aggregated Tau, coupled with a non-cell autonomous microglia activation.

Non-invasive, in vivo monitoring of neuronal transport impairment in a mouse model of tauopathy using MEMRI.

The impairment of axonal transport by overexpression or hyperphosphorylation of tau is well documented for in vitro conditions; however, only a few studies on this phenomenon have been conducted in vivo, using invasive procedures, and with contradictory results. Here we used the non-invasive, Manganese-Enhanced Magnetic Resonance Imaging technique (MEMRI), to study for the first time a pure model of tauopathy, the JNPL3 transgenic mouse line, which overexpresses a mutated (P301L) form of the human tau protein. We show progressive impairment in neuronal transport as tauopathy advances. These findings are further supported by a significant correlation between the severity of the impairment in neuronal transport assessed by MEMRI, and the degree of abnormal tau assessed by histology. Unlike conventional techniques that focus on axonal transport measurement, MEMRI can provide a global analysis of neuronal transport, i.e. from dendrites to axons and at the macroscopic scale of fiber tracts. Neuronal transport impairment has been shown to be a key pathogenic process in Alzheimer's disease and numerous other neurodegenerative disorders. Hence, MEMRI provides a promising set of functional biomarkers to be used during preclinical trials to facilitate the selection of new drugs aimed at restoring neuronal transport in neurodegenerative diseases.