Miltefosine as a PPM1A activator improves AD-like pathology in mice by alleviating tauopathy via microglia/neurons crosstalk

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.

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.