AdipoRon improves cognitive dysfunction of Alzheimer’s disease and rescues impaired neural stem cell proliferation through AdipoR1/AMPK pathway
Adult neurogenesis in hippocampus dentate gyrus (DG) is associated with the etiology on the early stage of Alzheimer's disease (AD). Factors that affect adult hippocampal neurogenesis have been shown to contribute to the neuropathology of AD. Adiponectin, a peptide hormone secreted by adipocyte...
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description | Adult neurogenesis in hippocampus dentate gyrus (DG) is associated with the etiology on the early stage of Alzheimer's disease (AD). Factors that affect adult hippocampal neurogenesis have been shown to contribute to the neuropathology of AD. Adiponectin, a peptide hormone secreted by adipocytes, plays a critical role in insulin sensitizing, anti-inflammatory, and anti-diabetic effects in peripheral tissues. We previously showed that AdipoRon, as an agonist of adiponectin, promotes neurite outgrowth under ischemia. However, the role of AdipoRon on neural stem cells (NSCs) proliferation and cognitive dysfunction in the early stage of AD remains unknown. In this study, we investigated the role of AdipoRon on cognitive dysfunction and deficits of NSCs proliferation in AD. The in vivo study showed that AdipoRon improved either cognitive dysfunction or impaired NSCs proliferation in hippocampus DG region in APP/PS1 transgenic (Tg) mice. In addition, AdipoRon treatment also suppressed the β-amyloid (Aβ) deposition and inhibited β-secretase 1(BACE1) expression in both cortex and hippocampus of APP/PS1 Tg mice. The in vitro study further suggested that AdipoRon significantly alleviated Aβ-induced cell viability and neuronal morphology in primary neurons. Both AdipoR1 silencing and compound C, inhibitor of AMPK, completely abolished the effect of AdipoRon. Interestingly, AdipoRon also protected the dissipation of the ΔΨm caused by Aβ toxicity in primary neurons, which was reversed by compound C. In NE-4C NSCs, AdipoRon significantly promoted the Aβ-induced impaired cell proliferation through AdipoR1/AMPK/CREB pathway. Furthermore, inhibition of AMPK by compound C also reversed the promotive effects of AdipoRon on cognition and proliferation of NSCs of APP/PS1 Tg mice, suggesting a AMPK-dependent mechanism by AdipoRon in AD in vivo. Taken together, these results suggested that AdipoRon alleviated the cognitive dysfunction of AD mice, inhibited the Aβ deposition by inhibiting BACE1 expression and promoted the impaired hippocampal NSCs proliferation on the early stage in vivo. The mechanisms involved activation of AdipoR1/AMPK pathway. Therefore, AdipoRon might be a potential candidate for the treatment of AD on the early stage.
•AdipoRon ameliorates cognitive deficit of APP/PS1 mice.•AdipoRon alleviates Aβ-induced impairment of neuronal survival and NSC proliferation.•AdipoRon promotes NSC proliferation through activating AMPK pathway. |
doi_str_mv | 10.1016/j.expneurol.2020.113249 |
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•AdipoRon ameliorates cognitive deficit of APP/PS1 mice.•AdipoRon alleviates Aβ-induced impairment of neuronal survival and NSC proliferation.•AdipoRon promotes NSC proliferation through activating AMPK pathway.</description><identifier>ISSN: 0014-4886</identifier><identifier>EISSN: 1090-2430</identifier><identifier>DOI: 10.1016/j.expneurol.2020.113249</identifier><identifier>PMID: 32070713</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Adiponectin ; Adiponectin receptor 1 ; AdipoRon ; Alzheimer's disease ; Amp-activated protein kinase ; Cognitive dysfunction ; Cyclic AMP response element-binding protein ; Mitochondrial function ; Neural stem cells proliferation ; β-Amyloid ; β-Secretase 1</subject><ispartof>Experimental neurology, 2020-05, Vol.327, p.113249-113249, Article 113249</ispartof><rights>2020 Elsevier Inc.</rights><rights>Copyright © 2020 Elsevier Inc. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c286t-bdd34e6ddefe2e92ffd0d55ca29bfefcdc89d7978821fed49860afbbf02720be3</citedby><cites>FETCH-LOGICAL-c286t-bdd34e6ddefe2e92ffd0d55ca29bfefcdc89d7978821fed49860afbbf02720be3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.expneurol.2020.113249$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,780,784,3550,27924,27925,45995</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/32070713$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Liu, Bin</creatorcontrib><creatorcontrib>Liu, Jing</creatorcontrib><creatorcontrib>Wang, Jian-gong</creatorcontrib><creatorcontrib>Liu, Cui-lan</creatorcontrib><creatorcontrib>Yan, Hai-jing</creatorcontrib><title>AdipoRon improves cognitive dysfunction of Alzheimer’s disease and rescues impaired neural stem cell proliferation through AdipoR1/AMPK pathway</title><title>Experimental neurology</title><addtitle>Exp Neurol</addtitle><description>Adult neurogenesis in hippocampus dentate gyrus (DG) is associated with the etiology on the early stage of Alzheimer's disease (AD). Factors that affect adult hippocampal neurogenesis have been shown to contribute to the neuropathology of AD. Adiponectin, a peptide hormone secreted by adipocytes, plays a critical role in insulin sensitizing, anti-inflammatory, and anti-diabetic effects in peripheral tissues. We previously showed that AdipoRon, as an agonist of adiponectin, promotes neurite outgrowth under ischemia. However, the role of AdipoRon on neural stem cells (NSCs) proliferation and cognitive dysfunction in the early stage of AD remains unknown. In this study, we investigated the role of AdipoRon on cognitive dysfunction and deficits of NSCs proliferation in AD. The in vivo study showed that AdipoRon improved either cognitive dysfunction or impaired NSCs proliferation in hippocampus DG region in APP/PS1 transgenic (Tg) mice. In addition, AdipoRon treatment also suppressed the β-amyloid (Aβ) deposition and inhibited β-secretase 1(BACE1) expression in both cortex and hippocampus of APP/PS1 Tg mice. The in vitro study further suggested that AdipoRon significantly alleviated Aβ-induced cell viability and neuronal morphology in primary neurons. Both AdipoR1 silencing and compound C, inhibitor of AMPK, completely abolished the effect of AdipoRon. Interestingly, AdipoRon also protected the dissipation of the ΔΨm caused by Aβ toxicity in primary neurons, which was reversed by compound C. In NE-4C NSCs, AdipoRon significantly promoted the Aβ-induced impaired cell proliferation through AdipoR1/AMPK/CREB pathway. Furthermore, inhibition of AMPK by compound C also reversed the promotive effects of AdipoRon on cognition and proliferation of NSCs of APP/PS1 Tg mice, suggesting a AMPK-dependent mechanism by AdipoRon in AD in vivo. Taken together, these results suggested that AdipoRon alleviated the cognitive dysfunction of AD mice, inhibited the Aβ deposition by inhibiting BACE1 expression and promoted the impaired hippocampal NSCs proliferation on the early stage in vivo. The mechanisms involved activation of AdipoR1/AMPK pathway. Therefore, AdipoRon might be a potential candidate for the treatment of AD on the early stage.
•AdipoRon ameliorates cognitive deficit of APP/PS1 mice.•AdipoRon alleviates Aβ-induced impairment of neuronal survival and NSC proliferation.•AdipoRon promotes NSC proliferation through activating AMPK pathway.</description><subject>Adiponectin</subject><subject>Adiponectin receptor 1</subject><subject>AdipoRon</subject><subject>Alzheimer's disease</subject><subject>Amp-activated protein kinase</subject><subject>Cognitive dysfunction</subject><subject>Cyclic AMP response element-binding protein</subject><subject>Mitochondrial function</subject><subject>Neural stem cells proliferation</subject><subject>β-Amyloid</subject><subject>β-Secretase 1</subject><issn>0014-4886</issn><issn>1090-2430</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><recordid>eNqFUc1u1DAQthCILoVXAB-5ZDt2skl8jCooiFYgBGfLscddr5I42MnS5dRX6JHX40nwNqVXTiN5vr_xR8gbBmsGrDzbrfFmHHAOvltz4OmV5bwQT8iKgYCMFzk8JSsAVmRFXZcn5EWMOwAQBa-ek5OcQwUVy1fkrjFu9F_9QF0_Br_HSLW_Htzk9kjNIdp50JNLa29p0_3aousx_Ln9HalxEVVEqgZDA0Y9J2rSUC6gocdoqqNxwp5q7DqatDtnMah7sWkb_Hy9pYs5O2uuvnyio5q2P9XhJXlmVRfx1cM8Jd_fv_t2_iG7_Hzx8by5zDSvyylrjckLLI1BixwFt9aA2Wy04qK1aLXRtTCVqOqaM4umEHUJyratBV5xaDE_JW8X3RTtRwo_yd7FY1Y1oJ-j5Pmm3ghRFpCg1QLVwccY0MoxuF6Fg2Qgj33InXzsQx77kEsfifn6wWRuezSPvH8FJECzADCduncYZNQOB40m_aOepPHuvyZ_AXYtpq8</recordid><startdate>202005</startdate><enddate>202005</enddate><creator>Liu, Bin</creator><creator>Liu, Jing</creator><creator>Wang, Jian-gong</creator><creator>Liu, Cui-lan</creator><creator>Yan, Hai-jing</creator><general>Elsevier Inc</general><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>202005</creationdate><title>AdipoRon improves cognitive dysfunction of Alzheimer’s disease and rescues impaired neural stem cell proliferation through AdipoR1/AMPK pathway</title><author>Liu, Bin ; Liu, Jing ; Wang, Jian-gong ; Liu, Cui-lan ; Yan, Hai-jing</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c286t-bdd34e6ddefe2e92ffd0d55ca29bfefcdc89d7978821fed49860afbbf02720be3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>Adiponectin</topic><topic>Adiponectin receptor 1</topic><topic>AdipoRon</topic><topic>Alzheimer's disease</topic><topic>Amp-activated protein kinase</topic><topic>Cognitive dysfunction</topic><topic>Cyclic AMP response element-binding protein</topic><topic>Mitochondrial function</topic><topic>Neural stem cells proliferation</topic><topic>β-Amyloid</topic><topic>β-Secretase 1</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Liu, Bin</creatorcontrib><creatorcontrib>Liu, Jing</creatorcontrib><creatorcontrib>Wang, Jian-gong</creatorcontrib><creatorcontrib>Liu, Cui-lan</creatorcontrib><creatorcontrib>Yan, Hai-jing</creatorcontrib><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Experimental neurology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Liu, Bin</au><au>Liu, Jing</au><au>Wang, Jian-gong</au><au>Liu, Cui-lan</au><au>Yan, Hai-jing</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>AdipoRon improves cognitive dysfunction of Alzheimer’s disease and rescues impaired neural stem cell proliferation through AdipoR1/AMPK pathway</atitle><jtitle>Experimental neurology</jtitle><addtitle>Exp Neurol</addtitle><date>2020-05</date><risdate>2020</risdate><volume>327</volume><spage>113249</spage><epage>113249</epage><pages>113249-113249</pages><artnum>113249</artnum><issn>0014-4886</issn><eissn>1090-2430</eissn><abstract>Adult neurogenesis in hippocampus dentate gyrus (DG) is associated with the etiology on the early stage of Alzheimer's disease (AD). Factors that affect adult hippocampal neurogenesis have been shown to contribute to the neuropathology of AD. Adiponectin, a peptide hormone secreted by adipocytes, plays a critical role in insulin sensitizing, anti-inflammatory, and anti-diabetic effects in peripheral tissues. We previously showed that AdipoRon, as an agonist of adiponectin, promotes neurite outgrowth under ischemia. However, the role of AdipoRon on neural stem cells (NSCs) proliferation and cognitive dysfunction in the early stage of AD remains unknown. In this study, we investigated the role of AdipoRon on cognitive dysfunction and deficits of NSCs proliferation in AD. The in vivo study showed that AdipoRon improved either cognitive dysfunction or impaired NSCs proliferation in hippocampus DG region in APP/PS1 transgenic (Tg) mice. In addition, AdipoRon treatment also suppressed the β-amyloid (Aβ) deposition and inhibited β-secretase 1(BACE1) expression in both cortex and hippocampus of APP/PS1 Tg mice. The in vitro study further suggested that AdipoRon significantly alleviated Aβ-induced cell viability and neuronal morphology in primary neurons. Both AdipoR1 silencing and compound C, inhibitor of AMPK, completely abolished the effect of AdipoRon. Interestingly, AdipoRon also protected the dissipation of the ΔΨm caused by Aβ toxicity in primary neurons, which was reversed by compound C. In NE-4C NSCs, AdipoRon significantly promoted the Aβ-induced impaired cell proliferation through AdipoR1/AMPK/CREB pathway. Furthermore, inhibition of AMPK by compound C also reversed the promotive effects of AdipoRon on cognition and proliferation of NSCs of APP/PS1 Tg mice, suggesting a AMPK-dependent mechanism by AdipoRon in AD in vivo. Taken together, these results suggested that AdipoRon alleviated the cognitive dysfunction of AD mice, inhibited the Aβ deposition by inhibiting BACE1 expression and promoted the impaired hippocampal NSCs proliferation on the early stage in vivo. The mechanisms involved activation of AdipoR1/AMPK pathway. Therefore, AdipoRon might be a potential candidate for the treatment of AD on the early stage.
•AdipoRon ameliorates cognitive deficit of APP/PS1 mice.•AdipoRon alleviates Aβ-induced impairment of neuronal survival and NSC proliferation.•AdipoRon promotes NSC proliferation through activating AMPK pathway.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>32070713</pmid><doi>10.1016/j.expneurol.2020.113249</doi><tpages>1</tpages></addata></record> |
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subjects | Adiponectin Adiponectin receptor 1 AdipoRon Alzheimer's disease Amp-activated protein kinase Cognitive dysfunction Cyclic AMP response element-binding protein Mitochondrial function Neural stem cells proliferation β-Amyloid β-Secretase 1 |
title | AdipoRon improves cognitive dysfunction of Alzheimer’s disease and rescues impaired neural stem cell proliferation through AdipoR1/AMPK pathway |
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