The TAU isoform 1N4R restores vulnerability of MAPT knockout human iPSC-derived neurons to Amyloid beta-induced neuronal dysfunction

Abstract

Abstract The microtubule-associated protein TAU is a key driver of the neurodegeneration observed in Alzheimer’s disease (AD). Normally, TAU stabilizes neuronal microtubules (MT) and promotes essential MT-associated functions. Alternative splicing of the TAU-encoding MAPT gene results in the expression of six isoforms in the human brain. Models of AD and TAU pathology to date are mostly based on rodents, which differ in their TAU isoform expression and often rely on the overexpression of mutant human TAU to develop hallmarks of AD. Moreover, recent results from murine neurons highlight that TAU isoforms are differentially localized within neurons and may have isoform-specific functions, but human cellular data is scarce. In this study, we generated MAPT KO human induced pluripotent stem cells using CRISPR/Cas9 and induced neuronal differentiation using Ngn2. Differentiated TAU KO neurons show no major abnormalities or changes in neuronal activity but sightly decreased neurite outgrowth and AIS length. Yet, TAU-depleted neurons are protected from AD-like stress, e.g, Amyloid-beta oligomer (AβO)-induced reduction of neuronal activity. Re-expression of most individual TAU isoforms was sufficient to rescue the changes in neurite and AIS development. However, the 1N4R-TAU isoform alone was sufficient to restore neuronal vulnerability to AD-like stress. In sum, we describe here for the first time a human iPSC-based MAPT KO/TAU depletion model to study the function of TAU isoforms and their role in AD pathology. Our results suggest that 1N4R-TAU is involved in early TAU-mediated toxicity and a potential target for future therapeutic strategies for AD.