Post by Amanda McFarlan
What's the science?
Alzheimer’s disease (AD) is a neurodegenerative disorder known to cause deficits in short-term memory, long-term memory and spatial memory. Neurofibrillary tangles, that arise due to the aggregation of hyperphosphorylated Tau proteins, are one of the main biomarkers of AD. Recent studies have shown that the bridging integrator 1 gene (BIN1) is associated with late-onset forms of AD and interacts directly with the Tau protein. This week in the Acta Neuropathologica, Sartori and colleagues investigated the role of overexpressed BIN1 in a mouse model of Tauopathy as well as the underlying molecular mechanisms regulating BIN1-Tau interactions.
How did they do it?
In the first set of experiments, the authors assessed the role of BIN1 expression levels on cognitive function using male and female mice from three different genetic strains: Tau mice (overexpressed the human MAPT gene to produce a Tauopathy model), Tau/BIN1 mice (overexpressed both human MAPT and human BIN1 genes) and control mice. They performed the novel object recognition and Morris water maze at 3, 6, 9, 12, and 15 months to assess the effect of BIN1 overexpression on short-term, non-spatial memory and long-term spatial memory, respectively. In the second set of experiments, the authors investigated the underlying mechanisms that modulate the interaction of BIN1 and Tau — they performed immunolabelling to quantify the level of Tau phosphorylation in the hippocampus. Next, they used proximity ligation assay and primary neuronal cultures to assess the effect of BIN1 overexpression on the amount and localization of BIN1-Tau complexes. It is known that phosphorylation of Tau prevents its interaction with BIN1. Therefore, the authors developed a semi-automated high-content screening approach to identify specific compounds in signaling pathways that may be involved in Tau phosphorylation. Finally, in the third set of experiments, the authors quantified the levels of total and phosphorylated BIN1 in human brain samples from 28 individuals (10 controls, 18 diagnosed with Alzheimer’s disease) with varying degrees of Tau pathology.
What did they find?
The authors found that short-term memory deficits were induced in male and female Tau mice starting at 9 months, while Tau/BIN1 mice showed short-term memory deficits as early as 3 months. Conversely, they determined that male Tau mice displayed long-term and spatial memory deficits at 12 months, while male Tau/BIN1 mice did not display any long-term or spatial memory deficits at any age. Together, these results suggest that overexpression of BIN1 worsens Tau pathology phenotypes for short-term memory deficits but rescues long-term and spatial memory deficits. Next, they revealed that Tau/BIN1 mice had significantly lower levels of Tau phosphorylation in the hippocampus compared to Tau mice (as determined by fewer cells with intracellular inclusions) and that Tau/BIN1 mice had a strong increase in the proximity ligation assay signal (amount of BIN1-Tau complexes) compared to Tau mice and controls.
Together, these results suggest that overexpression of BIN1 increases the number of BIN1-Tau complexes in the hippocampus which decreases the amount of phosphorylated Tau that can form toxic intracellular inclusions (i.e. protective against neurofibrillary tangles). Next, the authors determined that the signaling pathways regulated by Cyclosporin A (an inhibitor of the serine/threonine protein phosphatase Calcineurin) were important for mediating the interaction of BIN1 and Tau. They showed that dephosphorylation of BIN1 by Calcineurin on a cyclin-dependent kinase phosphorylation site at T348 promoted the open conformation of BIN1. Phosphorylation at this site increased the likelihood of BIN1 and Tau interactions. These findings suggest that Cyclosporin A mediates the interaction of BIN1 and Tau via the dephosphorylation of T348 by Calcineurin. Finally, the authors determined that although global levels of BIN1 were unchanged in AD conditions, a higher proportion of overall BIN1 levels were phosphorylated in individuals with AD compared to controls.
What's the impact?
This is the first study to show that the complex regulation of the interaction between BIN1 and Tau is involved in AD pathology. Mouse models revealed that overexpression of BIN1 had neuroprotective effects for Tau phenotypes including long-term and spatial memory deficits, and that this may be regulated by the interaction between BIN1 and Tau. Altogether, these findings provide important insight into the underlying mechanisms leading to AD pathology.
Sartori et al. BIN1 recovers tauopathy-induced long-term memory deficits in mice and interacts with Tau through Thr348 phosphorylation. Acta Neuropathologica (2019). Access the original scientific publication here.