Tofigh Nahid, Agahi Sadaf, Riazi Gholamhossein, Ghalamkar Moazzam Mahboobeh, Shahpasand Koorosh
Laboratory of Neuro-Organic Chemistry, Institute of Biochemistry and Biophysics (IBB), University of Tehran, Tehran 13561-457, Iran.
Department of Brain and Cognitive Sciences, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran 16635-148, Iran.
Biomolecules. 2025 Apr 15;15(4):585. doi: 10.3390/biom15040585.
Alzheimer's disease (AD) is a neurodegenerative disorder with no effective treatments. Hyperphosphorylation of tau protein contributes to neurodegeneration in AD. Previous studies have identified pT231-tau in the cis conformation as an early driver of neurodegeneration in tauopathy models. Here, we identify a novel neurotoxic pT231-tau conformer in human AD neurons, distinct from both cis and trans conformations, which we propose as the gauche pT231-tau conformer. Notably, levels of this conformer were elevated in neurons subjected to aging-associated stress. In order to confirm the stress, we examined p21 accumulation in both human iPSC-derived and mouse cortical neurons under aging stress. Targeted elimination of the gauche pT231-tau conformer mitigated neurodegeneration in human AD cultures. These findings suggest the gauche pT231-tau conformer plays a key role in tau-mediated neurodegeneration and may be a potential therapeutic target for AD.
阿尔茨海默病（AD）是一种没有有效治疗方法的神经退行性疾病。tau蛋白的过度磷酸化促成了AD中的神经退行性变。先前的研究已确定顺式构象的pT231-tau是tau蛋白病模型中神经退行性变的早期驱动因素。在此，我们在人类AD神经元中鉴定出一种新型神经毒性pT231-tau构象异构体，它不同于顺式和反式构象，我们将其命名为扭曲gauche pT231-tau构象异构体。值得注意的是，在经历与衰老相关应激的神经元中，这种构象异构体的水平升高。为了证实这种应激，我们检测了衰老应激下人诱导多能干细胞衍生神经元和小鼠皮质神经元中p21的积累情况。靶向消除扭曲gauche pT231-tau构象异构体可减轻人类AD培养物中的神经退行性变。这些发现表明，扭曲gauche pT231-tau构象异构体在tau介导的神经退行性变中起关键作用，可能是AD的一个潜在治疗靶点。
