Alzheimer’s Disease Risk Factor BIN1 Impacts Neuropathological Tau Propagation
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Mentor Information
Dr. Gopal Thinakaran
Description
Bridging INtegrator-1 (BIN1) is an adaptor protein found in neurons, microglia, and oligodendrocytes in the brain. BIN1 is the second most prevalent genetic risk factor associated with late-onset Alzheimer’s Disease (LOAD). Neuronal BIN1 localizes to presynaptic terminals and plays a role in excitatory synaptic transmission, whereas microglial BIN1 regulates neuroinflammatory activation. Previous studies have shown that neuronal BIN1 is required for hippocampal tau pathogenesis. However, the specific molecular mechanisms underlying BIN1’s function in tauopathy are still unknown. To investigate BIN1 function in trans-synaptic tau propagation in the brain, we applied stereotaxic unilateral hippocampal injection of mouse brain homogenates containing human pathogenic tau aggregates (tau seeds) into tau transgenic mice (PS19) followed by systematic analysis of tau pathology in serial brain sections. We found that minimal tau pathology was observed in 2-month-old un-injected PS19 mice but became evident in mice injected with tau seeds 60 days post-injection, confirming the spread of tau through connected brain regions. Interestingly, the loss of BIN1 expression in excitatory neurons in the forebrain of young PS19:Bin1 conditional knockout mice significantly reduced the propagation of tau pathology from the hippocampus to other cortical regions. Instead, we observed an accumulation of phosphorylated tau and pathological conformational tau in hippocampal CA1 pyramidal neurons in these mice, along with reduced activation of astrocytes. These findings suggest that excitatory neuronal BIN1 promotes the spread of pathogenic tau through connected brain regions and activates neuroinflammation. Therefore, targeting neuronal BIN1 could be a potential therapeutic approach for treating Alzheimer’s Disease.
Alzheimer’s Disease Risk Factor BIN1 Impacts Neuropathological Tau Propagation
Bridging INtegrator-1 (BIN1) is an adaptor protein found in neurons, microglia, and oligodendrocytes in the brain. BIN1 is the second most prevalent genetic risk factor associated with late-onset Alzheimer’s Disease (LOAD). Neuronal BIN1 localizes to presynaptic terminals and plays a role in excitatory synaptic transmission, whereas microglial BIN1 regulates neuroinflammatory activation. Previous studies have shown that neuronal BIN1 is required for hippocampal tau pathogenesis. However, the specific molecular mechanisms underlying BIN1’s function in tauopathy are still unknown. To investigate BIN1 function in trans-synaptic tau propagation in the brain, we applied stereotaxic unilateral hippocampal injection of mouse brain homogenates containing human pathogenic tau aggregates (tau seeds) into tau transgenic mice (PS19) followed by systematic analysis of tau pathology in serial brain sections. We found that minimal tau pathology was observed in 2-month-old un-injected PS19 mice but became evident in mice injected with tau seeds 60 days post-injection, confirming the spread of tau through connected brain regions. Interestingly, the loss of BIN1 expression in excitatory neurons in the forebrain of young PS19:Bin1 conditional knockout mice significantly reduced the propagation of tau pathology from the hippocampus to other cortical regions. Instead, we observed an accumulation of phosphorylated tau and pathological conformational tau in hippocampal CA1 pyramidal neurons in these mice, along with reduced activation of astrocytes. These findings suggest that excitatory neuronal BIN1 promotes the spread of pathogenic tau through connected brain regions and activates neuroinflammation. Therefore, targeting neuronal BIN1 could be a potential therapeutic approach for treating Alzheimer’s Disease.
