Human Stem Cell Study Reveals How Tau Fuels Alzheimer’s Damage

A study from the University of Cologne has provided new insights into how the tau protein contributes to Alzheimer’s disease. Using human induced pluripotent stem cells (iPSCs), researchers identified a specific form of tau, known as the 1N4R isoform, as a key driver of neuronal dysfunction in the presence of amyloid beta and phosphorylated tau aggregates. The findings were published in Alzheimer’s & Dementia.

The research, led by Dr Hans Zempel from the Institute of Human Genetics at the University of Cologne, highlights how different tau isoforms may influence neurodegenerative processes. The team’s use of advanced cell culture techniques provides a model for further exploration of tau’s role in disease progression.

Investigating tau’s role in neurodegeneration

Alzheimer’s disease is marked by the accumulation of protein clumps within brain cells, disrupting normal function and ultimately leading to cell death. Among these proteins, tau aggregates form neurofibrillary tangles, a hallmark of the disease. However, tau exists in multiple isoforms, and the specific contributions of each have remained unclear.

In this study, the researchers used CRISPR/Cas9 gene editing to generate iPSCs with modified tau expression. iPSCs are a type of stem cell derived from adult tissues, such as skin cells, which can be reprogrammed into neurons. This allowed the team to analyze the effects of different tau isoforms in human nerve cells. By expressing individual tau variants, they demonstrated that the 1N4R isoform specifically mediated the toxic effects of protein aggregation.

Live-cell imaging techniques revealed that neurons expressing 1N4R tau were particularly vulnerable to amyloid beta and phosphorylated tau accumulation. These findings suggest that the presence of this isoform could exacerbate the disease’s progression by increasing neuronal susceptibility to pathological protein interactions.

Implications for future research

The study underscores the importance of using human cell models to investigate neurodegenerative diseases. While animal models have provided valuable insights into Alzheimer’s, the complexity of human tau isoform expression has posed challenges for translating findings across species.

Further research is needed to determine how targeting 1N4R tau might inform therapeutic strategies. The next steps include validating these findings in appropriate animal models and exploring ways to modulate isoform expression. These efforts could contribute to the development of interventions aimed at reducing tau-mediated toxicity in Alzheimer’s disease.

Reference: Buchholz S, Kabbani MAA, Bell-Simons M, et al. The tau isoform 1N4R confers vulnerability of MAPT knockout human iPSC-derived neurons to amyloid beta and phosphorylated tau-induced neuronal dysfunction. Alzheimer’s Dementia. 2025;n/a(n/a):e14403. doi: 10.1002/alz.14403

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