Type I interferon (IFN-I) triggers necroptosis in macrophages infected with S. Typhimurium by an unclear mechanism. Hos et al. now demonstrate that RIP3 enhances the interaction of Nrf2 with Pgam5 in response to IFN-I signaling in S. Typhimurium–infected macrophages, which abates Nrf2-dependent cytoprotective pathways and increases cell death.

In the adult human brain, six isoforms of the microtubule-associated protein TAU are expressed, which result from alternative splicing of exons 2, 3, and 10 of the MAPT gene. These isoforms differ in the number of N-terminal inserts (0N, 1N, 2N) and C-terminal repeat domains (3R or 4R) and are differentially expressed depending on the brain region and developmental stage. Although all TAU isoforms can aggregate and form neurofibrillary tangles, some tauopathies, such as Pick’s disease and progressive supranuclear palsy, are characterized by the accumulation of specific TAU isoforms. The influence of the individual TAU isoforms in a cellular context, however, is understudied. In this report, we investigated the subcellular localization of the human-specific TAU isoforms in primary mouse neurons and analyzed TAU isoform-specific effects on cell area and microtubule dynamics in human SH-SY5Y neuroblastoma cells. Our results show that 2N-TAU isoforms are particularly retained from axonal sorting and that axonal enrichment is independent of the number of repeat domains, but that the additional repeat domain of 4R-TAU isoforms results in a general reduction of cell size and an increase of microtubule counts in cells expressing these specific isoforms. Our study points out that individual TAU isoforms may influence microtubule dynamics differentially both by different sorting patterns and by direct effects on microtubule dynamics.

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.