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...
Gespeichert in:
Veröffentlicht in: | The EMBO journal 2015-06, Vol.34 (12), p.1674-1686 |
---|---|
Hauptverfasser: | , , , , , , , , , , , , , , |
Format: | Artikel |
Sprache: | eng |
Schlagworte: | |
Online-Zugang: | Volltext bestellen |
Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
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 |
format | Article |
fullrecord | <record><control><sourceid>proquest_C6C</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_4475401</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>1688008770</sourcerecordid><originalsourceid>FETCH-LOGICAL-c5935-b69d5ae57bd1ab29279af7b6d03682b1c0adbd105f5758bd896855da977d4db13</originalsourceid><addsrcrecordid>eNqFkc1u1DAURiMEokNhzQ55ySat7cSxwwKJjtry04JUFcHOsuM7Mx4SO9hJIa8F79FnwiVlVDawsRc-57tX_rLsKcEHhFFGD6HT2wOKSSkEr9m9bEHKCucUc3Y_W2Bakbwkot7LHsW4xRgzwcnDbI-yuirLolhkm8sNoDgEiBGlo_cuAnIwBt9DP1gDaHlxgqxrAqgIEaluar01-fUP1Advxmaw3iE9JXk9tmqwbo2uf-YRkjAkA6lEXNlhepw9WKk2wpPbez_7eHJ8uXydn304fbN8dZY3rC5YrqvaMAWMa0OUpjXltVpxXRlcVIJq0mBl0hNmK8aZ0EbUlWDMqJpzUxpNiv3s5Zzbj7oD04AbgmplH2ynwiS9svLvF2c3cu2vZFlyVuKbgOe3AcF_HSEOsrOxgbZVDvwYJamEwFhwjhN6OKNN8DEGWO3GECx_9yNv-pG7fpLx7O52O_5PIQl4MQPfbAvT__Lk8fnR27vpeJZj8twagtz6Mbj03f9YKJ8VGwf4vpunwhdZ8YIz-en9qfzM-bsLel5KVvwC5enAyw</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1688008770</pqid></control><display><type>article</type><title>The stress response neuropeptide CRF increases amyloid-β production by regulating γ-secretase activity</title><source>Springer Nature OA/Free Journals</source><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</creator><creatorcontrib>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</creatorcontrib><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><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> |
fulltext | fulltext_linktorsrc |
identifier | ISSN: 0261-4189 |
ispartof | The EMBO journal, 2015-06, Vol.34 (12), p.1674-1686 |
issn | 0261-4189 1460-2075 |
language | eng |
recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_4475401 |
source | Springer Nature OA/Free Journals |
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 |
url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-14T23%3A21%3A33IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_C6C&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=The%20stress%20response%20neuropeptide%20CRF%20increases%20amyloid-%CE%B2%20production%20by%20regulating%20%CE%B3-secretase%20activity&rft.jtitle=The%20EMBO%20journal&rft.au=Park,%20Hyo-Jin&rft.date=2015-06-12&rft.volume=34&rft.issue=12&rft.spage=1674&rft.epage=1686&rft.pages=1674-1686&rft.issn=0261-4189&rft.eissn=1460-2075&rft_id=info:doi/10.15252/embj.201488795&rft_dat=%3Cproquest_C6C%3E1688008770%3C/proquest_C6C%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1688008770&rft_id=info:pmid/25964433&rfr_iscdi=true |