Institut Professeur Baulieu, Kremlin-Bicêtre, France.
Department of Biosciences, Biotechnology and Biopharmacology, UNIBA University, Bari, Italy.
J Alzheimers Dis. 2023;94(1):313-331. doi: 10.3233/JAD-230127.
Pathological tau proteins constitute neurofibrillary tangles that accumulate in tauopathies including Alzheimer's disease (AD), progressive supranuclear palsy (PSP), and familial frontotemporal lobar degeneration (FTLD-Tau). We previously showed that the FKBP52 immunophilin interacts functionally with tau and strongly decreases in AD brain neurons in correlation with tau deposition. We also reported that FKBP52 co-localizes with autophagy-lysosomal markers and an early pathological tau isoform in AD neurons, suggesting its involvement in autophagic tau clearance.
Our objective was to evaluate if differences in neuronal FKBP52 expression levels and subcellular localization might be detected in AD, PSP, familial FTLD-Tau, and in the hTau-P301 S mouse model compared to controls.
Cell by cell immunohistofluorescence analyses and quantification of FKBP52 were performed on postmortem brain samples of some human tauopathies and on hTau-P301 S mice spinal cords.
We describe a similar FKBP52 decrease and its localization with early pathological tau forms in the neuronal autophagy-lysosomal pathway in various tauopathies and hTau-P301 S mice. We find that FKBP52 decreases early during the pathologic process as it occurs in rare neurons with tau deposits in the marginally affected frontal cortex region of AD Braak IV brains and in the spinal cord of symptomless 1-month-old hTau-P301 S mice.
As FKBP52 plays a significant role in cellular signaling and conceivably in tau clearance, our data support the idea that the prevention of FKBP52 decrease or the restoration of its normal expression at early pathologic stages might represent a new potential therapeutic approach in tauopathies including AD, familial FTLD-Tau, and PSP.
病理性 tau 蛋白构成神经原纤维缠结，在包括阿尔茨海默病（AD）、进行性核上性麻痹（PSP）和家族性额颞叶变性（FTLD-Tau）在内的 tau 病中积累。我们之前表明，FKBP52 免疫亲和素与 tau 具有功能相互作用，并在 AD 大脑神经元中与 tau 沉积呈强相关的方式减少。我们还报告说，FKBP52 与自噬溶酶体标志物和 AD 神经元中的早期病理性 tau 同工型共定位，表明其参与自噬 tau 清除。
我们的目的是评估在 AD、PSP、家族性 FTLD-Tau 以及 hTau-P301S 小鼠模型中是否可以检测到神经元 FKBP52 表达水平和亚细胞定位的差异与对照相比。
对一些人类 tau 病的死后脑组织样本和 hTau-P301S 小鼠脊髓进行细胞间免疫荧光分析和 FKBP52 的定量。
我们描述了在各种 tau 病和 hTau-P301S 小鼠中，神经元自噬溶酶体途径中 FKBP52 的相似减少及其与早期病理性 tau 形式的定位。我们发现，FKBP52 在病理过程早期减少，因为它发生在 AD Braak IV 大脑边缘受累的额皮质区域和无症状 1 个月大的 hTau-P301S 小鼠脊髓中出现 tau 沉积的罕见神经元中。
由于 FKBP52 在细胞信号传导中起重要作用，并且可能在 tau 清除中起作用，我们的数据支持这样一种观点，即预防 FKBP52 减少或在早期病理阶段恢复其正常表达可能代表一种新的潜在治疗方法在包括 AD、家族性 FTLD-Tau 和 PSP 在内的 tau 病中。
