Department of Neuroscience, University of Minnesota, Minneapolis, Minnesota 55455.
Department of General Practice, The General Hospital of Western Theater Command, Chengdu 610083, China.
J Neurosci. 2024 Jul 10;44(28):e1215232024. doi: 10.1523/JNEUROSCI.1215-23.2024.
Tau pathologies are detected in the brains of some of the most common neurodegenerative diseases including Alzheimer's disease (AD), Lewy body dementia (LBD), chronic traumatic encephalopathy (CTE), and frontotemporal dementia (FTD). Tau proteins are expressed in six isoforms with either three or four microtubule-binding repeats (3R tau or 4R tau) due to alternative RNA splicing. AD, LBD, and CTE brains contain pathological deposits of both 3R and 4R tau. FTD patients can exhibit either 4R tau pathologies in most cases or 3R tau pathologies less commonly in Pick's disease, which is a subfamily of FTD. Here, we report the isoform-specific roles of tau in FTD. The P301L mutation, linked to familial 4R tau FTD, induces mislocalization of 4R tau to dendritic spines in primary hippocampal cultures that were prepared from neonatal rat pups of both sexes. Contrastingly, the G272V mutation, linked to familial Pick's disease, induces phosphorylation-dependent mislocalization of 3R tau but not 4R tau proteins to dendritic spines. The overexpression of G272V 3R tau but not 4R tau proteins leads to the reduction of dendritic spine density and suppression of mEPSCs in 5-week-old primary rat hippocampal cultures. The decrease in mEPSC amplitude caused by G272V 3R tau is dynamin-dependent whereas that caused by P301L 4R tau is dynamin-independent, indicating that the two tau isoforms activate different signaling pathways responsible for excitatory synaptic dysfunction. Our 3R and 4R tau studies here will shed new light on diverse mechanisms underlying FTD, AD, LBD, and CTE.
在一些最常见的神经退行性疾病的大脑中检测到 tau 病理学，包括阿尔茨海默病（AD）、路易体痴呆（LBD）、慢性创伤性脑病（CTE）和额颞叶痴呆（FTD）。由于 RNA 剪接的差异，tau 蛋白表达为具有三个或四个微管结合重复（3R tau 或 4R tau）的 6 种同工型。AD、LBD 和 CTE 大脑中都存在 3R 和 4R tau 的病理性沉积物。FTD 患者通常表现为 4R tau 病理学，在 Pick 病中则较少见，Pick 病是 FTD 的一个亚家族。在这里，我们报告了 tau 在 FTD 中的同工型特异性作用。与家族性 4R tau FTD 相关的 P301L 突变导致 4R tau 在原代海马培养物的树突棘中错误定位，这些培养物是从新生大鼠的两性幼崽中制备的。相比之下，与家族性 Pick 病相关的 G272V 突变导致 3R tau 但不是 4R tau 蛋白依赖磷酸化的错误定位到树突棘。G272V 3R tau 的过表达而不是 4R tau 蛋白导致 5 周龄原代大鼠海马培养物中的树突棘密度降低和 mEPSC 抑制。G272V 3R tau 引起的 mEPSC 幅度降低是 dynamin 依赖性的，而 P301L 4R tau 引起的降低是 dynamin 非依赖性的，表明两种 tau 同工型激活了导致兴奋性突触功能障碍的不同信号通路。我们在这里进行的 3R 和 4R tau 研究将为 FTD、AD、LBD 和 CTE 的不同机制提供新的见解。
