关键词： AAV, Adeno-associated virus AD, Alzheimer's disease ALP, Alkaline phosphatase ALT, Alanine aminotransferase AST, Aspartate aminotransferase Akt, V-akt routine thymoma viral oncogene homolog Alzheimer's disease Aβ, Amyloid-β CDK5, Cyclin-dependent protein kinase-5 CNS, Central nervous system CX3CR1 CX3CR1, C-X3-C Motif Chemokine Receptor 1 CaMKII, Calcium/calmodulin-dependent protein kinase II DYRK1A, Dual-specificity tyrosine phosphorylation-regulated kinase-1A GSK3β, Glycogen synthase kinase 3β LTP, Long-term potentiation MST, Microscale thermophoresis MWM, Morris water maze Miltefosine NF-kB, Nuclear factor-κb NFTs, Neurofibrillary tangles NLRP3 NLRP3, Nod-like receptor protein 3 NOR, New object recognition PP2, Protein phosphatase 2 PPM1A PPM1A, Phosphatase magnesium-dependent 1A PSD95, Postsynaptic density protein 95 SYN, Synaptophysin Tauopathy fEPSPs, Field excitatory postsynaptic potentials

来  源：   DOI：10.1016/j.bbih.2022.100546   PDF(Pubmed)

Abstract：
Alzheimer\'s disease (AD) is a progressively neurodegenerative disease without effective treatment. Here, we reported that the levels of expression and enzymatic activity of phosphatase magnesium-dependent 1A (PPM1A) were both repressed in brains of AD patient postmortems and 3 × Tg-AD mice, and treatment of adeno-associated virus (AAV)-ePHP-overexpression (OE)-PPM1A for brain-specific PPM1A overexpression or the new discovered PPM1A activator Miltefosine (MF, FDA approved oral anti-leishmanial drug) for PPM1A enzymatic activation improved the AD-like pathology in 3 × Tg-AD mice. The mechanism was intensively investigated by assay against the 3 × Tg-AD mice with brain-specific PPM1A knockdown (KD) through AAV-ePHP-KD-PPM1A injection. MF alleviated neuronal tauopathy involving microglia/neurons crosstalk by both promoting microglial phagocytosis of tau oligomers via PPM1A/Nuclear factor-κb (NF-κB)/C-X3-C Motif Chemokine Receptor 1 (CX3CR1) signaling and inhibiting neuronal tau hyperphosphorylation via PPM1A/NLR Family Pyrin Domain Containing 3 (NLRP3)/tau axis. MF suppressed microglial NLRP3 inflammasome activation by both inhibiting NLRP3 transcription via PPM1A/NF-κB/NLRP3 pathway in priming step and promoting PPM1A binding to NLRP3 to interfere NLRP3 inflammasome assembly in assembly step. Our results have highly addressed that PPM1A activation shows promise as a therapeutic strategy for AD and highlighted the potential of MF in treating this disease.
摘要：
阿尔茨海默病(Alzheimer’sdisease,AD)是一种无有效治疗的进行性神经退行性疾病。这里,我们报道了磷酸酶镁依赖性1A（PPM1A）的表达水平和酶活性在AD患者病后和3×Tg-AD小鼠的大脑中均被抑制，和腺相关病毒（AAV）-ePHP过表达（OE）-PPM1A治疗脑特异性PPM1A过表达或新发现的PPM1A激活剂米替福辛（MF，FDA批准用于PPM1A酶促激活的口服抗利什曼尼药）改善了3×Tg-AD小鼠的AD样病理。通过AAV-ePHP-KD-PPM1A注射对具有脑特异性PPM1A敲低(KD)的3×Tg-AD小鼠的测定来深入研究该机制。MF通过PPM1A/核因子κb（NF-κB）/C-X3-C基序趋化因子受体1（CX3CR1）信号传导促进tau寡聚体的小胶质细胞吞噬作用，并通过PPM1A/NLR家族PyrinP3包含3（NLRR结构域）/tau轴抑制神经元tau过度磷酸化，缓解了涉及小胶质细胞/神经元串扰的神经元tau病。MF通过在引发步骤中通过PPM1A/NF-κB/NLRP3途径抑制NLRP3转录并促进PPM1A与NLRP3结合以干扰NLRP3在组装步骤中的炎症小体组装，从而抑制了小胶质NLRP3炎症小体的激活。我们的结果已经高度阐明了PPM1A激活显示出作为AD的治疗策略的希望，并强调了MF在治疗这种疾病中的潜力。
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