Tau protein becomes phosphorylated and aggregates into neurofibrillary tangles in the aging brain. This harms neurons, and along with inflammation is the dominant pathology in later stages of Alzheimer's disease and other tauopathies. Researchers here engineer neurons to harbor each of the six possible tau isoforms, one by one, and demonstrate that only one of those six different isoforms of tau is a cause of pathology. It remains to be seen as to how this will shape further work leading to new forms of therapy.
The formation of neurofibrillary tangles (NFTs) by hyperphosphorylated tau is the hallmark of Alzheimer's disease (AD) and other neurodegenerative diseases. Under pathological conditions, such as in the presence of toxic amyloid beta (Aβ) oligomers (AβOs), tau becomes hyperphosphorylated, altering axonal microtubule dynamics, causing axonal transport deficits, synapse loss, and ultimately neuronal death and cognitive decline.
In the adult human brain, six tau isoforms originate from alternative splicing of exons 2, 3, and 10 of the MAPT gene. Notably, in the adult human brain 1N tau isoforms (1N3R/1N4R) account for 50% of tau, and 2N tau isoforms are the least expressed isoforms (5%-10%), while in rodents 2N isoforms account for the majority of expressed tau. In rodents and derived neurons, the isoforms differ in intracellular localization, suggesting isoform-specific tau functions. The significance of the isoform expression ratio for neuronal health is underscored by mutations in the MAPT gene that affect its splicing: Changes leading to an imbalance of 3R to 4R tau expression have been directly associated with frontotemporal dementia (FTD) and tauopathies can be classified by the isoforms present in the pathological NFTs.
Rodents, which express almost exclusively 4R tau isoforms (whereas human neurons express 3R and 4R tau), are often used to better understand disease pathology and identify potential therapeutic targets. However, rodents do not naturally develop dementia, and tauopathy models rely on the overexpression of single (mutant/ human) tau isoforms to study disease mechanisms. The contribution of the different tau isoforms to tau physiology and toxicity in disease remains unclear.
Here, we generated tau knockout (KO) human induced pluripotent stem cells (hiPSCs) modified to be easily differentiated into glutamatergic neurons. Tau KO neurons showed impairments of neurite growth and axon initial segment formation, restored by re-expression of individual tau isoforms. Tau KO neurons were protected against AβO-induced neuronal dysfunction and transcriptomic changes, and only the 1N4R tau isoform fully restored the AβO vulnerability of tau KO neurons, based on the higher basal phosphorylation levels of 1N4R tau within the microtubule binding domain, suggesting that this isoform is less microtubule bound compared to other isoforms. All in all, we describe a human tau KO neuronal model and identify 1N4R as a critical mediator of tau toxicity in hiPSC-derived neurons, implying 1N4R tau to be a potential therapeutic target for Alzheimer's disease.
Link: https://doi.org/10.1002/alz.14403
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