Tau lesions, characterized by Tau protein aggregation, are a group of heterogeneous neurodegenerative diseases. The most common Tau degenerative diseases include Alzheimer's disease (AD) and frontotemporal lobe degenerative diseases with Tau lesions (frontotemporal lobar degenera- tion with Tau pathology, referred to as FTLD-Tau), such as Pick's disease (PiD), cortical basal degeneration (CBD), progressive supranuclear paralysis (progressive supranuclear palsy, referred to as PSP) and so on. Tau is encoded by a single gene (MAPT). Due to the alternative splicing of exon 10, six isomers are produced, including three (3R) or four (4R) microtubule binding repeats [2]. There are three subtypes of Tau disease, namely, 3R, 4R and 3R/4R mixed type, and different Tau fiber structures have been revealed by cryogenic electron microscopy (cryo-EM). The Tau fibers in AD (3R/4R), PiD (3R), CBD (4R) and PSP (4R) are different in structure. Among the MAPT mutations that lead to familial cases of FTLD-Tau, many mutations change the proportion of 3R-4R [5LJ6]; several mutations, including P301 Sbinl, are located in exon 10 [7], so they are 4R specific.

Neurons derived from human induced pluripotent stem cells (Human induced pluripotent stem cell, referred to as hiPSC) are of little value in simulating nervous system diseases, including but not limited to Tau disease. Combined with CRISPR-Cas9 technology, the neuron platform derived from iPSC can achieve accurate disease modeling and functional genomics analysis through allelic modification, so that disease-related regulatory factors can be identified. However, even after long-term culture, the expression of 4R Tau in iPSC-derived neurons is very low, so it is not suitable to simulate 4R Tau diseases such as PSP. The low level of Tau containing exon 10 also limits their ability to mimic dominant familial FTLD-Tau mutations in exon 10. In addition, it is difficult to reproduce stable Tau aggregation in human iPSC-derived neurons. Although no insoluble Tau aggregation was observed in MAPT-P301L or MAPT-IVS10 + 16 iPSC neurons, a small number of Tau inclusion bodies could be observed after 120 days. An important factor leading to this phenomenon may be the lack of 4R Tau in neurons derived from iPSC.

Recently, the Shiaoching Gong and Li Gan research groups from Weill Cornell Medicine in New York published an article entitled Human iPSC 4R tauopathy model uncovers modifiers of tau propagation on Cell, and successfully established a robust and scalable human iPSC 4R Tau disease model.

Tau disease is an age-related neurodegenerative disease, the specific mechanism of which is still little known, one of the reasons is the lack of appropriate human models. The authors engineered the neuronal cell line derived from hiPSC to express 4R Tau and 4R Tau carrying P301S MAPT mutation when differentiating into neurons. After inoculating Tau fibers, 4R-P301S neurons gradually produced Tau inclusion bodies and reproduced the phenotypic characteristics of Tau disease, including shared transcriptome characteristics, autophagy body accumulation, gradual diffusion of Tau aggregation, abnormal neural activity and dysfunction of internal lysosome pathway. Next, the authors carried out CRISPRi screening of genes related to Tau pathobiology and identified more than 500 possible genetic modifiers for Tau transmission, including genes in the cascade of retinol transporter VPS29 and ubiquitin folding modification protein (UFMylation). In PSP and AD brains, the cascade response of ubiquitin folding modified proteins is altered in neurons with neurofibrillary tangles. Inhibition of the cascade reaction of ubiquitin folding modified proteins in vitro and in vivo can effectively inhibit the spread of Tau.

To sum up, the authors present a robust and scalable human iPSC 4R Tau disease model. Through the engineering hiPSC cell line, 4R Tau and 4R Tau (4R-P301S) carrying P301S MAPT mutation were expressed during neuronal differentiation, and it was determined that 4R-P301S neurons could mimic the pathological characteristics of Tau disease to some extent. In addition, the authors also integrate CRISPRi and functional genome screening to identify new molecules and pathways involved in Tau diseases, which provides new ideas for the discovery of potential treatment strategies.

Of course, there are two main defects in this model: one is that it is unable to reproduce the characteristics of aging neurons in the human brain, and aging is one of the causes of AD; the other is that it does not reproduce the Tau lesion of AD, because the Tau carried by AD patients is 3R/4R complex, while this model only expresses 4R. These two points are also the key directions to upgrade this model.

Original link: https://doi.org/10.1016/j.cell.2024.03.015

References:

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