PMID- 36388134
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20221119
IS  - 2666-3546 (Electronic)
IS  - 2666-3546 (Linking)
VI  - 26
DP  - 2022 Dec
TI  - Miltefosine as a PPM1A activator improves AD-like pathology in mice by 
      alleviating tauopathy via microglia/neurons crosstalk.
PG  - 100546
LID - 10.1016/j.bbih.2022.100546 [doi]
LID - 100546
AB  - 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 x 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 x Tg-AD mice. The mechanism was intensively investigated 
      by assay against the 3 x 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-kappab (NF-kappaB)/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-kappaB/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.
CI  - (c) 2022 The Authors.
FAU - Lv, Jianlu
AU  - Lv J
AD  - Jiangsu Key Laboratory of Drug Target and Drug for Degenerative Diseases, Nanjing 
      University of Chinese Medicine, Nanjing, 210023, China.
AD  - College of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, 
      China.
FAU - Shen, Xingyi
AU  - Shen X
AD  - Jiangsu Key Laboratory of Drug Target and Drug for Degenerative Diseases, Nanjing 
      University of Chinese Medicine, Nanjing, 210023, China.
FAU - Shen, Xinya
AU  - Shen X
AD  - Jiangsu Key Laboratory of Drug Target and Drug for Degenerative Diseases, Nanjing 
      University of Chinese Medicine, Nanjing, 210023, China.
FAU - Li, Xiaoqian
AU  - Li X
AD  - Jiangsu Key Laboratory of Drug Target and Drug for Degenerative Diseases, Nanjing 
      University of Chinese Medicine, Nanjing, 210023, China.
FAU - Jin, Zhuoying
AU  - Jin Z
AD  - Jiangsu Key Laboratory of Drug Target and Drug for Degenerative Diseases, Nanjing 
      University of Chinese Medicine, Nanjing, 210023, China.
FAU - Ouyang, Xingnan
AU  - Ouyang X
AD  - Jiangsu Key Laboratory of Drug Target and Drug for Degenerative Diseases, Nanjing 
      University of Chinese Medicine, Nanjing, 210023, China.
FAU - Lu, Jian
AU  - Lu J
AD  - Jiangsu Key Laboratory of Drug Target and Drug for Degenerative Diseases, Nanjing 
      University of Chinese Medicine, Nanjing, 210023, China.
FAU - Zhu, Danyang
AU  - Zhu D
AD  - Jiangsu Key Laboratory of Drug Target and Drug for Degenerative Diseases, Nanjing 
      University of Chinese Medicine, Nanjing, 210023, China.
FAU - Wang, Jiaying
AU  - Wang J
AD  - Jiangsu Key Laboratory of Drug Target and Drug for Degenerative Diseases, Nanjing 
      University of Chinese Medicine, Nanjing, 210023, China.
FAU - Shen, Xu
AU  - Shen X
AD  - Jiangsu Key Laboratory of Drug Target and Drug for Degenerative Diseases, Nanjing 
      University of Chinese Medicine, Nanjing, 210023, China.
AD  - National Key Laboratory on Technologies for Chinese Medicine Pharmaceutical 
      Process Control and Intelligent Manufacture, Nanjing, 210023, China.
LA  - eng
PT  - Journal Article
DEP - 20221029
PL  - United States
TA  - Brain Behav Immun Health
JT  - Brain, behavior, & immunity - health
JID - 101759062
PMC - PMC9650016
OTO - NOTNLM
OT  - AAV, Adeno-associated virus
OT  - AD, Alzheimer's disease
OT  - ALP, Alkaline phosphatase
OT  - ALT, Alanine aminotransferase
OT  - AST, Aspartate aminotransferase
OT  - Akt, V-akt routine thymoma viral oncogene homolog
OT  - Alzheimer's disease
OT  - Abeta, Amyloid-beta
OT  - CDK5, Cyclin-dependent protein kinase-5
OT  - CNS, Central nervous system
OT  - CX3CR1
OT  - CX3CR1, C-X3-C Motif Chemokine Receptor 1
OT  - CaMKII, Calcium/calmodulin-dependent protein kinase II
OT  - DYRK1A, Dual-specificity tyrosine phosphorylation-regulated kinase-1A
OT  - GSK3beta, Glycogen synthase kinase 3beta
OT  - LTP, Long-term potentiation
OT  - MST, Microscale thermophoresis
OT  - MWM, Morris water maze
OT  - Miltefosine
OT  - NF-kB, Nuclear factor-kappab
OT  - NFTs, Neurofibrillary tangles
OT  - NLRP3
OT  - NLRP3, Nod-like receptor protein 3
OT  - NOR, New object recognition
OT  - PP2, Protein phosphatase 2
OT  - PPM1A
OT  - PPM1A, Phosphatase magnesium-dependent 1A
OT  - PSD95, Postsynaptic density protein 95
OT  - SYN, Synaptophysin
OT  - Tauopathy
OT  - fEPSPs, Field excitatory postsynaptic potentials
COIS- The authors declare that they have no known competing financial interests or 
      personal relationships that could have appeared to influence the work reported in 
      this paper.
EDAT- 2022/11/18 06:00
MHDA- 2022/11/18 06:01
PMCR- 2022/10/29
CRDT- 2022/11/17 12:07
PHST- 2022/06/16 00:00 [received]
PHST- 2022/10/10 00:00 [revised]
PHST- 2022/10/23 00:00 [accepted]
PHST- 2022/11/17 12:07 [entrez]
PHST- 2022/11/18 06:00 [pubmed]
PHST- 2022/11/18 06:01 [medline]
PHST- 2022/10/29 00:00 [pmc-release]
AID - S2666-3546(22)00136-3 [pii]
AID - 100546 [pii]
AID - 10.1016/j.bbih.2022.100546 [doi]
PST - epublish
SO  - Brain Behav Immun Health. 2022 Oct 29;26:100546. doi: 10.1016/j.bbih.2022.100546. 
      eCollection 2022 Dec.