Abstract
Polymorphisms associated with BIN1 (bridging integrator 1) confer the second greatest risk for developing late-onset Alzheimer’s disease. The biological consequences of this genetic variation are not fully understood; however, BIN1 is a binding partner for tau. Tau is normally a highly soluble cytoplasmic protein, but in Alzheimer’s disease, tau is abnormally phosphorylated and accumulates at synapses to exert synaptotoxicity. The purpose of this study was to determine whether alterations in BIN1 and tau in Alzheimer’s disease promote the damaging redistribution of tau to synapses, as a mechanism by which BIN1 polymorphisms may increase the risk of developing Alzheimer’s disease. We show that BIN1 is lost from the cytoplasmic fraction of Alzheimer’s disease cortex, and this is accompanied by the progressive mislocalization of phosphorylated tau to synapses. We confirmed proline 216 in tau as critical for tau interaction with the BIN1-SH3 domain and showed that the phosphorylation of tau disrupts this binding, suggesting that tau phosphorylation in Alzheimer’s disease disrupts tau–BIN1 associations. Moreover, we show that BIN1 knockdown in rat primary neurons to mimic BIN1 loss in Alzheimer’s disease brain causes the damaging accumulation of phosphorylated tau at synapses and alterations in dendritic spine morphology. We also observed reduced release of tau from neurons upon BIN1 silencing, suggesting that BIN1 loss disrupts the function of extracellular tau. Together, these data indicate that polymorphisms associated with BIN1 that reduce BIN1 protein levels in the brain likely act synergistically with increased tau phosphorylation to increase the risk of Alzheimer’s disease by disrupting cytoplasmic tau–BIN1 interactions, promoting the damaging mis-sorting of phosphorylated tau to synapses to alter synapse structure and reducing the release of physiological forms of tau to disrupt tau function.
Highlights
Tauopathies including Alzheimer’s disease are characterized by tau protein modifications that affect normal tau interactions and localization and lead to the development of neurofibrillary pathology (Guo et al, 2017)
Our results suggest that bridging integrator 1 (BIN1) and tau interact predominantly when tau is dephosphorylated in the cytoplasm and that altered tau phosphorylation, together with BIN1 loss in Alzheimer’s disease, allows tau to be mislocalized to synapses where it is detrimental to synapse health
We found that P216 of tau interacts with the BIN1-src homology 3 (SH3) and that interactions between these two proteins are disrupted when tau phosphorylation is increased in primary neurons
Summary
Tauopathies including Alzheimer’s disease are characterized by tau protein modifications that affect normal tau interactions and localization and lead to the development of neurofibrillary pathology (Guo et al, 2017). Developing a better understanding of the causes of tau protein redistribution to synapses may elucidate potential new treatment strategies for Alzheimer’s disease and related tauopathies. Recent genome-wide association studies have identified several gene variants that increase the risk of developing Alzheimer’s disease. Rare variants in coding regions of BIN1 have been identified (Vardarajan et al, 2015); the more common BIN1 variants are upstream of the gene and do not affect protein structure. These may affect the tissue-specific splicing or expression of the cytoplasmic membrane-binding BIN1 protein, which is known to play important roles in endocytosis and subcellular trafficking (Prokic et al, 2014). The expression of the longer neuronal isoform of BIN1 is decreased and the shorter glial isoforms are increased in Alzheimer’s disease brain (Glennon et al, 2013; Holler et al, 2014; De Rossi et al, 2016)
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