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. Be...

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Veröffentlicht in:Journal of neurochemistry 2017-09, Vol.142 (5), p.734-746
Hauptverfasser: 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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container_issue 5
container_start_page 734
container_title Journal of neurochemistry
container_volume 142
creator Kim, Young Doo
Jeong, Eun Il
Nah, Jihoon
Yoo, Seung‐Min
Lee, Won Jae
Kim, Youbin
Moon, Seowon
Hong, Se‐Hoon
Jung, Yong‐Keun
description 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. Because autophagy‐based AD therapy with mTOR as a target has side effects, other alternatives are needed. We found that pimozide increased autophagic flux through the activation of the AMPK‐ULK1 axis. Through this process, pimozide reduced levels of abnormally phosphorylated tau aggregates and rescued memory impairments in AD mouse model, providing insight into a therapeutics for tau‐mediated neuropathology in AD.
doi_str_mv 10.1111/jnc.14109
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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. Because autophagy‐based AD therapy with mTOR as a target has side effects, other alternatives are needed. We found that pimozide increased autophagic flux through the activation of the AMPK‐ULK1 axis. 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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. Because autophagy‐based AD therapy with mTOR as a target has side effects, other alternatives are needed. We found that pimozide increased autophagic flux through the activation of the AMPK‐ULK1 axis. 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control</subject><subject>Mice</subject><subject>Mice, Inbred BALB C</subject><subject>Mice, Inbred C57BL</subject><subject>Mice, Transgenic</subject><subject>Neurodegenerative diseases</subject><subject>Neurofibrillary tangles</subject><subject>Neurological diseases</subject><subject>Oligomers</subject><subject>Patients</subject><subject>Phagocytosis</subject><subject>Pharmacology</subject><subject>Phosphorylation</subject><subject>pimozide</subject><subject>Pimozide - pharmacology</subject><subject>Pimozide - therapeutic use</subject><subject>Protein kinase</subject><subject>Proteins</subject><subject>Rapamycin</subject><subject>Side effects</subject><subject>tau</subject><subject>Tau protein</subject><subject>tau Proteins - antagonists &amp; inhibitors</subject><subject>tau Proteins - metabolism</subject><subject>TOR protein</subject><issn>0022-3042</issn><issn>1471-4159</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp1kE1OAzEMhSMEglJYcAEUiRWLgTjJNMkSVfwKAQtYj9IkAynMpExmCmWFOAFn4Ug9CYECO7yxJX9-th9CW0D2IMX-uDZ7wIGoJdQDLiDjkKtl1COE0owRTtfQeoxjQmDAB7CK1qgcMKq46KG3K1-FF28dbpztjIu4Dc_e4DI0VcShxK3usK_xte6GDFfeODz1Gufz1w-sratD9LXDVajD5C7EyZ1u3fz1XZvWT1Np8aQJrUvz977W8atVOeu_O7pr04y-nW2glVI_RLf5k_vo5ujweniSnV8enw4PzjPDpFRZboFawXOZg5AClAZgubAlU1xaqZlwzIz0wLCcWSko0wzcSJROkZGWhjLWRzsL3XTTY-diW4xD19RpZQGKKgFUEZ6o3QVlmhBj48pi0vhKN7MCSPHldpHcLr7dTuz2j2I3Sn_9kb_2JmB_ATz5Bzf7X6k4uxguJD8Bbv2M4g</recordid><startdate>201709</startdate><enddate>201709</enddate><creator>Kim, Young Doo</creator><creator>Jeong, Eun Il</creator><creator>Nah, Jihoon</creator><creator>Yoo, Seung‐Min</creator><creator>Lee, Won Jae</creator><creator>Kim, Youbin</creator><creator>Moon, Seowon</creator><creator>Hong, Se‐Hoon</creator><creator>Jung, Yong‐Keun</creator><general>Blackwell Publishing Ltd</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QR</scope><scope>7TK</scope><scope>7U7</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>P64</scope><orcidid>https://orcid.org/0000-0002-9686-3120</orcidid></search><sort><creationdate>201709</creationdate><title>Pimozide reduces toxic forms of tau in TauC3 mice via 5′ adenosine monophosphate‐activated protein kinase‐mediated autophagy</title><author>Kim, Young Doo ; 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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. Because autophagy‐based AD therapy with mTOR as a target has side effects, other alternatives are needed. We found that pimozide increased autophagic flux through the activation of the AMPK‐ULK1 axis. Through this process, pimozide reduced levels of abnormally phosphorylated tau aggregates and rescued memory impairments in AD mouse model, providing insight into a therapeutics for tau‐mediated neuropathology in AD.</abstract><cop>England</cop><pub>Blackwell Publishing Ltd</pub><pmid>28632947</pmid><doi>10.1111/jnc.14109</doi><tpages>13</tpages><orcidid>https://orcid.org/0000-0002-9686-3120</orcidid><oa>free_for_read</oa></addata></record>
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subjects Activation
Adenosine kinase
Adenosine monophosphate
Aggregates
Alzheimer's disease
AMP
AMP-Activated Protein Kinases - metabolism
Animal models
Animals
Autophagy
Autophagy - drug effects
Autophagy - physiology
Autophagy-Related Protein-1 Homolog - metabolism
Caspase
Cells, Cultured
Dopamine
Dopamine Antagonists - pharmacology
Dopamine Antagonists - therapeutic use
Dopamine D2 receptors
Female
Flux
HeLa Cells
Humans
Inhibition
Kinases
Male
Memory
Memory Disorders - metabolism
Memory Disorders - prevention & control
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
Mice, Transgenic
Neurodegenerative diseases
Neurofibrillary tangles
Neurological diseases
Oligomers
Patients
Phagocytosis
Pharmacology
Phosphorylation
pimozide
Pimozide - pharmacology
Pimozide - therapeutic use
Protein kinase
Proteins
Rapamycin
Side effects
tau
Tau protein
tau Proteins - antagonists & inhibitors
tau Proteins - metabolism
TOR protein
title Pimozide reduces toxic forms of tau in TauC3 mice via 5′ adenosine monophosphate‐activated protein kinase‐mediated autophagy
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