The stress response neuropeptide CRF increases amyloid-β production by regulating γ-secretase activity

The biological underpinnings linking stress to Alzheimer's disease (AD) risk are poorly understood. We investigated how corticotrophin releasing factor (CRF), a critical stress response mediator, influences amyloid‐β (Aβ) production. In cells, CRF treatment increases Aβ production and triggers...

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Veröffentlicht in:The EMBO journal 2015-06, Vol.34 (12), p.1674-1686
Hauptverfasser: Park, Hyo-Jin, Ran, Yong, Jung, Joo In, Holmes, Oliver, Price, Ashleigh R, Smithson, Lisa, Ceballos-Diaz, Carolina, Han, Chul, Wolfe, Michael S, Daaka, Yehia, Ryabinin, Andrey E, Kim, Seong-Hun, Hauger, Richard L, Golde, Todd E, Felsenstein, Kevin M
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container_end_page 1686
container_issue 12
container_start_page 1674
container_title The EMBO journal
container_volume 34
creator Park, Hyo-Jin
Ran, Yong
Jung, Joo In
Holmes, Oliver
Price, Ashleigh R
Smithson, Lisa
Ceballos-Diaz, Carolina
Han, Chul
Wolfe, Michael S
Daaka, Yehia
Ryabinin, Andrey E
Kim, Seong-Hun
Hauger, Richard L
Golde, Todd E
Felsenstein, Kevin M
description The biological underpinnings linking stress to Alzheimer's disease (AD) risk are poorly understood. We investigated how corticotrophin releasing factor (CRF), a critical stress response mediator, influences amyloid‐β (Aβ) production. In cells, CRF treatment increases Aβ production and triggers CRF receptor 1 (CRFR1) and γ‐secretase internalization. Co‐immunoprecipitation studies establish that γ‐secretase associates with CRFR1; this is mediated by β‐arrestin binding motifs. Additionally, CRFR1 and γ‐secretase co‐localize in lipid raft fractions, with increased γ‐secretase accumulation upon CRF treatment. CRF treatment also increases γ‐secretase activity in vitro , revealing a second, receptor‐independent mechanism of action. CRF is the first endogenous neuropeptide that can be shown to directly modulate γ‐secretase activity. Unexpectedly, CRFR1 antagonists also increased Aβ. These data collectively link CRF to increased Aβ through γ‐secretase and provide mechanistic insight into how stress may increase AD risk. They also suggest that direct targeting of CRF might be necessary to effectively modulate this pathway for therapeutic benefit in AD, as CRFR1 antagonists increase Aβ and in some cases preferentially increase Aβ42 via complex effects on γ‐secretase. Synopsis Excessive activation of the hypothalamic–pituitary–adrenal (HPA) stress axis may be a risk factor for Alzheimer's disease. Stress exacerbates amyloid‐β (Aβ) accumulation in various animal models. Here we show that: Corticotropin releasing factor (CRF), a critical stress response mediator, increases Aβ production in cells and non‐transgenic mice. γ‐secretase interacts with CRF receptor 1 (CRFR1) through β‐arrestins. Upon CRF binding to CRFR1, γ‐secretase–CRFR1 complex moves into lipid rafts and endosomes where γ‐secretase activity increases. CRF and CRFR antagonists activate γ‐secretase in vitro through CRFR1‐independent mechanisms. Graphical Abstract The critical stress mediator corticotropin releasing factor (CRF) increases amyloid‐β production by altering γ‐secretase localization and activity, thus providing a link between stress and amyloid‐β pathology.
doi_str_mv 10.15252/embj.201488795
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We investigated how corticotrophin releasing factor (CRF), a critical stress response mediator, influences amyloid‐β (Aβ) production. In cells, CRF treatment increases Aβ production and triggers CRF receptor 1 (CRFR1) and γ‐secretase internalization. Co‐immunoprecipitation studies establish that γ‐secretase associates with CRFR1; this is mediated by β‐arrestin binding motifs. Additionally, CRFR1 and γ‐secretase co‐localize in lipid raft fractions, with increased γ‐secretase accumulation upon CRF treatment. CRF treatment also increases γ‐secretase activity in vitro , revealing a second, receptor‐independent mechanism of action. CRF is the first endogenous neuropeptide that can be shown to directly modulate γ‐secretase activity. Unexpectedly, CRFR1 antagonists also increased Aβ. These data collectively link CRF to increased Aβ through γ‐secretase and provide mechanistic insight into how stress may increase AD risk. They also suggest that direct targeting of CRF might be necessary to effectively modulate this pathway for therapeutic benefit in AD, as CRFR1 antagonists increase Aβ and in some cases preferentially increase Aβ42 via complex effects on γ‐secretase. Synopsis Excessive activation of the hypothalamic–pituitary–adrenal (HPA) stress axis may be a risk factor for Alzheimer's disease. Stress exacerbates amyloid‐β (Aβ) accumulation in various animal models. Here we show that: Corticotropin releasing factor (CRF), a critical stress response mediator, increases Aβ production in cells and non‐transgenic mice. γ‐secretase interacts with CRF receptor 1 (CRFR1) through β‐arrestins. Upon CRF binding to CRFR1, γ‐secretase–CRFR1 complex moves into lipid rafts and endosomes where γ‐secretase activity increases. CRF and CRFR antagonists activate γ‐secretase in vitro through CRFR1‐independent mechanisms. Graphical Abstract The critical stress mediator corticotropin releasing factor (CRF) increases amyloid‐β production by altering γ‐secretase localization and activity, thus providing a link between stress and amyloid‐β pathology.</description><identifier>ISSN: 0261-4189</identifier><identifier>EISSN: 1460-2075</identifier><identifier>DOI: 10.15252/embj.201488795</identifier><identifier>PMID: 25964433</identifier><language>eng</language><publisher>London: Blackwell Publishing Ltd</publisher><subject>Alzheimer Disease - etiology ; Alzheimer Disease - metabolism ; Amyloid beta-Peptides - biosynthesis ; Amyloid Precursor Protein Secretases - metabolism ; amyloid-β ; Analysis of Variance ; Animals ; Blotting, Western ; corticotrophin releasing factor ; Corticotropin-Releasing Hormone - metabolism ; Cyclic AMP - metabolism ; EMBO27 ; Enzyme-Linked Immunosorbent Assay ; HEK293 Cells ; Humans ; Hypothalamo-Hypophyseal System - physiology ; Immunoprecipitation ; Membrane Microdomains - metabolism ; Mice ; Mice, Inbred C57BL ; Microscopy, Fluorescence ; Models, Biological ; Pituitary-Adrenal System - physiology ; Real-Time Polymerase Chain Reaction ; Receptors, Corticotropin-Releasing Hormone - metabolism ; stress ; Stress, Physiological - physiology ; β-arrestin ; γ-secretase</subject><ispartof>The EMBO journal, 2015-06, Vol.34 (12), p.1674-1686</ispartof><rights>The Authors 2015</rights><rights>2015 The Authors</rights><rights>2015 The Authors.</rights><rights>2015 The Authors 2015</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c5935-b69d5ae57bd1ab29279af7b6d03682b1c0adbd105f5758bd896855da977d4db13</citedby><cites>FETCH-LOGICAL-c5935-b69d5ae57bd1ab29279af7b6d03682b1c0adbd105f5758bd896855da977d4db13</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4475401/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4475401/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,315,728,781,785,886,1418,1434,27929,27930,41125,42194,45579,45580,46414,46838,51581,53796,53798</link.rule.ids><linktorsrc>$$Uhttps://doi.org/10.15252/embj.201488795$$EView_record_in_Springer_Nature$$FView_record_in_$$GSpringer_Nature</linktorsrc><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25964433$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Park, Hyo-Jin</creatorcontrib><creatorcontrib>Ran, Yong</creatorcontrib><creatorcontrib>Jung, Joo In</creatorcontrib><creatorcontrib>Holmes, Oliver</creatorcontrib><creatorcontrib>Price, Ashleigh R</creatorcontrib><creatorcontrib>Smithson, Lisa</creatorcontrib><creatorcontrib>Ceballos-Diaz, Carolina</creatorcontrib><creatorcontrib>Han, Chul</creatorcontrib><creatorcontrib>Wolfe, Michael S</creatorcontrib><creatorcontrib>Daaka, Yehia</creatorcontrib><creatorcontrib>Ryabinin, Andrey E</creatorcontrib><creatorcontrib>Kim, Seong-Hun</creatorcontrib><creatorcontrib>Hauger, Richard L</creatorcontrib><creatorcontrib>Golde, Todd E</creatorcontrib><creatorcontrib>Felsenstein, Kevin M</creatorcontrib><title>The stress response neuropeptide CRF increases amyloid-β production by regulating γ-secretase activity</title><title>The EMBO journal</title><addtitle>EMBO J</addtitle><addtitle>EMBO J</addtitle><description>The biological underpinnings linking stress to Alzheimer's disease (AD) risk are poorly understood. We investigated how corticotrophin releasing factor (CRF), a critical stress response mediator, influences amyloid‐β (Aβ) production. In cells, CRF treatment increases Aβ production and triggers CRF receptor 1 (CRFR1) and γ‐secretase internalization. Co‐immunoprecipitation studies establish that γ‐secretase associates with CRFR1; this is mediated by β‐arrestin binding motifs. Additionally, CRFR1 and γ‐secretase co‐localize in lipid raft fractions, with increased γ‐secretase accumulation upon CRF treatment. CRF treatment also increases γ‐secretase activity in vitro , revealing a second, receptor‐independent mechanism of action. CRF is the first endogenous neuropeptide that can be shown to directly modulate γ‐secretase activity. Unexpectedly, CRFR1 antagonists also increased Aβ. These data collectively link CRF to increased Aβ through γ‐secretase and provide mechanistic insight into how stress may increase AD risk. They also suggest that direct targeting of CRF might be necessary to effectively modulate this pathway for therapeutic benefit in AD, as CRFR1 antagonists increase Aβ and in some cases preferentially increase Aβ42 via complex effects on γ‐secretase. Synopsis Excessive activation of the hypothalamic–pituitary–adrenal (HPA) stress axis may be a risk factor for Alzheimer's disease. Stress exacerbates amyloid‐β (Aβ) accumulation in various animal models. Here we show that: Corticotropin releasing factor (CRF), a critical stress response mediator, increases Aβ production in cells and non‐transgenic mice. γ‐secretase interacts with CRF receptor 1 (CRFR1) through β‐arrestins. Upon CRF binding to CRFR1, γ‐secretase–CRFR1 complex moves into lipid rafts and endosomes where γ‐secretase activity increases. CRF and CRFR antagonists activate γ‐secretase in vitro through CRFR1‐independent mechanisms. Graphical Abstract The critical stress mediator corticotropin releasing factor (CRF) increases amyloid‐β production by altering γ‐secretase localization and activity, thus providing a link between stress and amyloid‐β pathology.</description><subject>Alzheimer Disease - etiology</subject><subject>Alzheimer Disease - metabolism</subject><subject>Amyloid beta-Peptides - biosynthesis</subject><subject>Amyloid Precursor Protein Secretases - metabolism</subject><subject>amyloid-β</subject><subject>Analysis of Variance</subject><subject>Animals</subject><subject>Blotting, Western</subject><subject>corticotrophin releasing factor</subject><subject>Corticotropin-Releasing Hormone - metabolism</subject><subject>Cyclic AMP - metabolism</subject><subject>EMBO27</subject><subject>Enzyme-Linked Immunosorbent Assay</subject><subject>HEK293 Cells</subject><subject>Humans</subject><subject>Hypothalamo-Hypophyseal System - physiology</subject><subject>Immunoprecipitation</subject><subject>Membrane Microdomains - metabolism</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Microscopy, Fluorescence</subject><subject>Models, Biological</subject><subject>Pituitary-Adrenal System - physiology</subject><subject>Real-Time Polymerase Chain Reaction</subject><subject>Receptors, Corticotropin-Releasing Hormone - metabolism</subject><subject>stress</subject><subject>Stress, Physiological - physiology</subject><subject>β-arrestin</subject><subject>γ-secretase</subject><issn>0261-4189</issn><issn>1460-2075</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkc1u1DAURiMEokNhzQ55ySat7cSxwwKJjtry04JUFcHOsuM7Mx4SO9hJIa8F79FnwiVlVDawsRc-57tX_rLsKcEHhFFGD6HT2wOKSSkEr9m9bEHKCucUc3Y_W2Bakbwkot7LHsW4xRgzwcnDbI-yuirLolhkm8sNoDgEiBGlo_cuAnIwBt9DP1gDaHlxgqxrAqgIEaluar01-fUP1Advxmaw3iE9JXk9tmqwbo2uf-YRkjAkA6lEXNlhepw9WKk2wpPbez_7eHJ8uXydn304fbN8dZY3rC5YrqvaMAWMa0OUpjXltVpxXRlcVIJq0mBl0hNmK8aZ0EbUlWDMqJpzUxpNiv3s5Zzbj7oD04AbgmplH2ynwiS9svLvF2c3cu2vZFlyVuKbgOe3AcF_HSEOsrOxgbZVDvwYJamEwFhwjhN6OKNN8DEGWO3GECx_9yNv-pG7fpLx7O52O_5PIQl4MQPfbAvT__Lk8fnR27vpeJZj8twagtz6Mbj03f9YKJ8VGwf4vpunwhdZ8YIz-en9qfzM-bsLel5KVvwC5enAyw</recordid><startdate>20150612</startdate><enddate>20150612</enddate><creator>Park, Hyo-Jin</creator><creator>Ran, Yong</creator><creator>Jung, Joo In</creator><creator>Holmes, Oliver</creator><creator>Price, Ashleigh R</creator><creator>Smithson, Lisa</creator><creator>Ceballos-Diaz, Carolina</creator><creator>Han, Chul</creator><creator>Wolfe, Michael S</creator><creator>Daaka, Yehia</creator><creator>Ryabinin, Andrey E</creator><creator>Kim, Seong-Hun</creator><creator>Hauger, Richard L</creator><creator>Golde, Todd E</creator><creator>Felsenstein, Kevin M</creator><general>Blackwell Publishing Ltd</general><general>Nature Publishing Group UK</general><general>BlackWell Publishing Ltd</general><scope>BSCLL</scope><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>7X8</scope><scope>5PM</scope></search><sort><creationdate>20150612</creationdate><title>The stress response neuropeptide CRF increases amyloid-β production by regulating γ-secretase activity</title><author>Park, Hyo-Jin ; Ran, Yong ; Jung, Joo In ; Holmes, Oliver ; Price, Ashleigh R ; Smithson, Lisa ; Ceballos-Diaz, Carolina ; Han, Chul ; Wolfe, Michael S ; Daaka, Yehia ; Ryabinin, Andrey E ; Kim, Seong-Hun ; Hauger, Richard L ; Golde, Todd E ; Felsenstein, Kevin M</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c5935-b69d5ae57bd1ab29279af7b6d03682b1c0adbd105f5758bd896855da977d4db13</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Alzheimer Disease - etiology</topic><topic>Alzheimer Disease - metabolism</topic><topic>Amyloid beta-Peptides - biosynthesis</topic><topic>Amyloid Precursor Protein Secretases - metabolism</topic><topic>amyloid-β</topic><topic>Analysis of Variance</topic><topic>Animals</topic><topic>Blotting, Western</topic><topic>corticotrophin releasing factor</topic><topic>Corticotropin-Releasing Hormone - metabolism</topic><topic>Cyclic AMP - metabolism</topic><topic>EMBO27</topic><topic>Enzyme-Linked Immunosorbent Assay</topic><topic>HEK293 Cells</topic><topic>Humans</topic><topic>Hypothalamo-Hypophyseal System - physiology</topic><topic>Immunoprecipitation</topic><topic>Membrane Microdomains - metabolism</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Microscopy, Fluorescence</topic><topic>Models, Biological</topic><topic>Pituitary-Adrenal System - physiology</topic><topic>Real-Time Polymerase Chain Reaction</topic><topic>Receptors, Corticotropin-Releasing Hormone - metabolism</topic><topic>stress</topic><topic>Stress, Physiological - physiology</topic><topic>β-arrestin</topic><topic>γ-secretase</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Park, Hyo-Jin</creatorcontrib><creatorcontrib>Ran, Yong</creatorcontrib><creatorcontrib>Jung, Joo In</creatorcontrib><creatorcontrib>Holmes, Oliver</creatorcontrib><creatorcontrib>Price, Ashleigh R</creatorcontrib><creatorcontrib>Smithson, Lisa</creatorcontrib><creatorcontrib>Ceballos-Diaz, Carolina</creatorcontrib><creatorcontrib>Han, Chul</creatorcontrib><creatorcontrib>Wolfe, Michael S</creatorcontrib><creatorcontrib>Daaka, Yehia</creatorcontrib><creatorcontrib>Ryabinin, Andrey E</creatorcontrib><creatorcontrib>Kim, Seong-Hun</creatorcontrib><creatorcontrib>Hauger, Richard L</creatorcontrib><creatorcontrib>Golde, Todd E</creatorcontrib><creatorcontrib>Felsenstein, Kevin M</creatorcontrib><collection>Istex</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>The EMBO journal</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext_linktorsrc</fulltext></delivery><addata><au>Park, Hyo-Jin</au><au>Ran, Yong</au><au>Jung, Joo In</au><au>Holmes, Oliver</au><au>Price, Ashleigh R</au><au>Smithson, Lisa</au><au>Ceballos-Diaz, Carolina</au><au>Han, Chul</au><au>Wolfe, Michael S</au><au>Daaka, Yehia</au><au>Ryabinin, Andrey E</au><au>Kim, Seong-Hun</au><au>Hauger, Richard L</au><au>Golde, Todd E</au><au>Felsenstein, Kevin M</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The stress response neuropeptide CRF increases amyloid-β production by regulating γ-secretase activity</atitle><jtitle>The EMBO journal</jtitle><stitle>EMBO J</stitle><addtitle>EMBO J</addtitle><date>2015-06-12</date><risdate>2015</risdate><volume>34</volume><issue>12</issue><spage>1674</spage><epage>1686</epage><pages>1674-1686</pages><issn>0261-4189</issn><eissn>1460-2075</eissn><abstract>The biological underpinnings linking stress to Alzheimer's disease (AD) risk are poorly understood. We investigated how corticotrophin releasing factor (CRF), a critical stress response mediator, influences amyloid‐β (Aβ) production. In cells, CRF treatment increases Aβ production and triggers CRF receptor 1 (CRFR1) and γ‐secretase internalization. Co‐immunoprecipitation studies establish that γ‐secretase associates with CRFR1; this is mediated by β‐arrestin binding motifs. Additionally, CRFR1 and γ‐secretase co‐localize in lipid raft fractions, with increased γ‐secretase accumulation upon CRF treatment. CRF treatment also increases γ‐secretase activity in vitro , revealing a second, receptor‐independent mechanism of action. CRF is the first endogenous neuropeptide that can be shown to directly modulate γ‐secretase activity. Unexpectedly, CRFR1 antagonists also increased Aβ. These data collectively link CRF to increased Aβ through γ‐secretase and provide mechanistic insight into how stress may increase AD risk. They also suggest that direct targeting of CRF might be necessary to effectively modulate this pathway for therapeutic benefit in AD, as CRFR1 antagonists increase Aβ and in some cases preferentially increase Aβ42 via complex effects on γ‐secretase. Synopsis Excessive activation of the hypothalamic–pituitary–adrenal (HPA) stress axis may be a risk factor for Alzheimer's disease. Stress exacerbates amyloid‐β (Aβ) accumulation in various animal models. Here we show that: Corticotropin releasing factor (CRF), a critical stress response mediator, increases Aβ production in cells and non‐transgenic mice. γ‐secretase interacts with CRF receptor 1 (CRFR1) through β‐arrestins. Upon CRF binding to CRFR1, γ‐secretase–CRFR1 complex moves into lipid rafts and endosomes where γ‐secretase activity increases. CRF and CRFR antagonists activate γ‐secretase in vitro through CRFR1‐independent mechanisms. Graphical Abstract The critical stress mediator corticotropin releasing factor (CRF) increases amyloid‐β production by altering γ‐secretase localization and activity, thus providing a link between stress and amyloid‐β pathology.</abstract><cop>London</cop><pub>Blackwell Publishing Ltd</pub><pmid>25964433</pmid><doi>10.15252/embj.201488795</doi><tpages>13</tpages><oa>free_for_read</oa></addata></record>
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subjects Alzheimer Disease - etiology
Alzheimer Disease - metabolism
Amyloid beta-Peptides - biosynthesis
Amyloid Precursor Protein Secretases - metabolism
amyloid-β
Analysis of Variance
Animals
Blotting, Western
corticotrophin releasing factor
Corticotropin-Releasing Hormone - metabolism
Cyclic AMP - metabolism
EMBO27
Enzyme-Linked Immunosorbent Assay
HEK293 Cells
Humans
Hypothalamo-Hypophyseal System - physiology
Immunoprecipitation
Membrane Microdomains - metabolism
Mice
Mice, Inbred C57BL
Microscopy, Fluorescence
Models, Biological
Pituitary-Adrenal System - physiology
Real-Time Polymerase Chain Reaction
Receptors, Corticotropin-Releasing Hormone - metabolism
stress
Stress, Physiological - physiology
β-arrestin
γ-secretase
title The stress response neuropeptide CRF increases amyloid-β production by regulating γ-secretase activity
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