Tau deficiency protects human neurons from Abeta‐induced reduction of network activity

Abstract Background One hallmark of many neurodegenerative diseases, such as Alzheimer’s disease (AD), is the formation of neurofibrillary tangles by hyperphosphorylated Tau in the brain, resulting in neuronal death and cognitive decline. In the adult human brain, six Tau‐isoforms are expressed, originating from alternative splicing of exons 2, 3, and 10 of the MAPT gene. The isoforms differ in the number of N‐terminal inserts (0, 1, or 2N) and the C‐terminal repeat number (3 or 4R). Recent results from murine neurons highlight that the six human‐specific isoforms are differentially localized within neurons and influence microtubule dynamics in an isoform‐specific manner. In this study, we generated a human neuronal model system to further characterize the human‐specific Tau‐isoforms under basic and pathological conditions. Method We successfully generated three Tau KO hiPSC cell lines derived from Ngn2‐WTC11 cells using CRISPR/Cas9 and characterized the generated cell lines using genetic, biochemical and microscopy‐based methods. Result No difference between Tau KO and WT hiPSCs was observed in the capability of neuronal differentiation or neuronal morphology. Interestingly, Tau KO neurons were shown to be resistant to an Abeta‐induced reduction of network activity. Initial results from re‐expressed Tau‐isoforms in these neurons support the differential localization of the isoforms observed previously. Further experiments will investigate the isoform‐specific role of Tau regarding microtubule dynamics, axonal branching, and synapse formation under basal and pathological conditions. Conclusion Tau KO hiPSCs are a versatile tool to study basic as well as pathological functions of Tau. Expected results will provide a major understanding of Tau function and help identifying potential therapeutic targets for the treatment of AD and related neurodegenerative diseases.