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Publication Date : 2017/06/20
Pimozide reduces toxic forms of tau in TauC3 mice via 5' adenosine monophosphate-activated protein kinase-mediated autophagy.
In neurodegenerative diseases like Alzheimer's disease (AD), tau is hyperphosphorylated and forms aggregates and neurofibrillary tangles in affected neurons. Autophagy is critical to clear the aggregates of disease-associated proteins and is often altered in patients and animal models of AD. Because mechanistic target of rapamycin (mTOR) negatively regulates autophagy and is hyperactive in the brains of patients with AD, mTOR is an attractive therapeutic target for AD. However, pharmacological strategies to increase autophagy by targeting mTOR inhibition cause various side effects. Therefore, autophagy activation mediated by non-mTOR pathways is a new option for autophagy-based AD therapy. Here, we report that pimozide activates autophagy to rescue tau pathology in an AD model. Pimozide increased autophagic flux through the activation of the AMPK-Unc-51 like autophagy activating kinase 1 (ULK1) axis, but not of mTOR, in neuronal cells, and this function was independent of dopamine D2 receptor inhibition. Pimozide reduced levels of abnormally phosphorylated tau aggregates in neuronal cells. Further, daily intraperitoneal (i.p.) treatment of pimozide led to a recovery from memory deficits of TauC3 mice expressing a caspase-cleaved form of tau. In the brains of these mice, we found increased phosphorylation of AMPK1 and ULK1, and reduced levels of the soluble oligomers and NP40-insoluble aggregates of abnormally phosphorylated tau. Together, these results suggest that pimozide rescues memory impairments in TauC3 mice and reduces tau aggregates by increasing autophagic flux through the mTOR-independent AMPK-ULK1 axis.
Authors : Kim Young Doo , Jeong Eun Il , Nah Jihoon , Yoo Seung-Min , Lee Won Jae , Kim Youbin , Moon Seowon , Hong Se-Hoon , Jung Yong-Keun ,
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[KCNH2 ERG ERG1 HERG] Potassium voltage-gated channel subfamily H member 2 (Eag homolog) (Ether-a-go-go-related gene potassium channel 1) (ERG-1) (Eag-related protein 1) (Ether-a-go-go-related protein 1) (H-ERG) (hERG-1) (hERG1) (Voltage-gated potassium channel subunit Kv11.1)
[DRD2] D(2) dopamine receptor (Dopamine D2 receptor)
[CYP3A4 CYP3A3] Cytochrome P450 3A4 (EC 1.14.13.-) (1,8-cineole 2-exo-monooxygenase) (EC 1.14.13.157) (Albendazole monooxygenase) (EC 1.14.13.32) (Albendazole sulfoxidase) (CYPIIIA3) (CYPIIIA4) (Cholesterol 25-hydroxylase) (EC 1.14.14.1) (Cytochrome P450 3A3) (Cytochrome P450 HLp) (Cytochrome P450 NF-25) (Cytochrome P450-PCN1) (Nifedipine oxidase) (Quinine 3-monooxygenase) (EC 1.14.13.67) (Taurochenodeoxycholate 6-alpha-hydroxylase) (EC 1.14.13.97)
[CYP1A2] Cytochrome P450 1A2 (EC 1.14.14.1) (CYPIA2) (Cholesterol 25-hydroxylase) (Cytochrome P(3)450) (Cytochrome P450 4) (Cytochrome P450-P3)
[CYP2D6 CYP2DL1] Cytochrome P450 2D6 (EC 1.14.14.1) (CYPIID6) (Cholesterol 25-hydroxylase) (Cytochrome P450-DB1) (Debrisoquine 4-hydroxylase)
[DRD3] D(3) dopamine receptor (Dopamine D3 receptor)
[ABCB1 MDR1 PGY1] Multidrug resistance protein 1 (EC 3.6.3.44) (ATP-binding cassette sub-family B member 1) (P-glycoprotein 1) (CD antigen CD243)
[CYP2C19] Cytochrome P450 2C19 (EC 1.14.13.-) ((R)-limonene 6-monooxygenase) (EC 1.14.13.80) ((S)-limonene 6-monooxygenase) (EC 1.14.13.48) ((S)-limonene 7-monooxygenase) (EC 1.14.13.49) (CYPIIC17) (CYPIIC19) (Cytochrome P450-11A) (Cytochrome P450-254C) (Mephenytoin 4-hydroxylase)
[CYP2E1 CYP2E] Cytochrome P450 2E1 (EC 1.14.13.-) (4-nitrophenol 2-hydroxylase) (EC 1.14.13.n7) (CYPIIE1) (Cytochrome P450-J)
[CYP3A5] Cytochrome P450 3A5 (EC 1.14.14.1) (CYPIIIA5) (Cytochrome P450 HLp2) (Cytochrome P450-PCN3)
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