KIBRA repairs synaptic plasticity and promotes resilience to tauopathy-related memory loss
Synaptic plasticity is obstructed by pathogenic tau in the brain, representing a key mechanism that underlies memory loss in Alzheimer's disease (AD) and related tauopathies. Here, we found that reduced levels of the memory-associated protein KIdney/BRAin (KIBRA) in the brain and increased KIBR...
Gespeichert in:
| Veröffentlicht in: | The Journal of clinical investigation 2024-02, Vol.134 (3), p.1-18 |
|---|---|
| Hauptverfasser: | , , , , , , , , , , , , , , , , , , , |
| Format: | Artikel |
| Sprache: | eng |
| Schlagworte: | |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | 18 |
|---|---|
| container_issue | 3 |
| container_start_page | 1 |
| container_title | The Journal of clinical investigation |
| container_volume | 134 |
| creator | Kauwe, Grant Pareja-Navarro, Kristeen A Yao, Lei Chen, Jackson H Wong, Ivy Saloner, Rowan Cifuentes, Helen Nana, Alissa L Shah, Samah Li, Yaqiao Le, David Spina, Salvatore Grinberg, Lea T Seeley, William W Kramer, Joel H Sacktor, Todd C Schilling, Birgit Gan, Li Casaletto, Kaitlin B Tracy, Tara E |
| description | Synaptic plasticity is obstructed by pathogenic tau in the brain, representing a key mechanism that underlies memory loss in Alzheimer's disease (AD) and related tauopathies. Here, we found that reduced levels of the memory-associated protein KIdney/BRAin (KIBRA) in the brain and increased KIBRA protein levels in cerebrospinal fluid are associated with cognitive impairment and pathological tau levels in disease. We next defined a mechanism for plasticity repair in vulnerable neurons using the C-terminus of the KIBRA protein (CT-KIBRA). We showed that CT-KIBRA restored plasticity and memory in transgenic mice expressing pathogenic human tau; however, CT-KIBRA did not alter tau levels or prevent tau-induced synapse loss. Instead, we found that CT-KIBRA stabilized the protein kinase Mζ (PKMζ) to maintain synaptic plasticity and memory despite tau-mediated pathogenesis. Thus, our results distinguished KIBRA both as a biomarker of synapse dysfunction and as the foundation for a synapse repair mechanism to reverse cognitive impairment in tauopathy. |
| doi_str_mv | 10.1172/JCI169064 |
| format | Article |
| fullrecord | <record><control><sourceid>gale_proqu</sourceid><recordid>TN_cdi_proquest_miscellaneous_2921117714</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><galeid>A785207130</galeid><sourcerecordid>A785207130</sourcerecordid><originalsourceid>FETCH-LOGICAL-c5033-430a6addccf067f76648a8eac13064a011a8b2fe71672b4486729ff099c007d83</originalsourceid><addsrcrecordid>eNqN0ktv1DAQAGALUdFSOPAHkCUkRA8pduLEznFZ8dhSqVJ5HLhEs85k15UTB9uRyL_Hq5bSRXtAPoxlfR6Nx0PIC87OOZf524vlilc1q8QjcsLLUmUqL9TjB_tj8jSEG8a4EKV4Qo4Lldd1qeQJ-fF59e56QT2OYHygYR5gjEbT0UJI0cSZwtDS0bveRQwJBmMNDhppdDTC5EaI2znzaCFiS3vsnZ-pdSE8I0cd2IDP7-Ip-fbh_dflp-zy6uNqubjMdMmKIhMFgwraVuuOVbKTVSUUKATNi_QiYJyDWucdSl7JfC2ESqHuOlbXmjHZquKUvLnNm4r8OWGITW-CRmthQDeFJq9zntokuUj01T_0xk1-SNXtVM1FWeXlX7UBi40ZOhc96F3SZiFVmTOZSksqO6A2OKAH6wbsTDre8-cHfFot9kYfvHC2dyGZiL_iBqYQmtWX6_-3V9_37esHdotg4zY4O0XjhnAwqfbpOz12zehND35uOGt2g9fcD16yL-86O617bO_ln0krfgNX4Mz4</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2929145625</pqid></control><display><type>article</type><title>KIBRA repairs synaptic plasticity and promotes resilience to tauopathy-related memory loss</title><source>MEDLINE</source><source>Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals</source><source>PubMed Central</source><source>Alma/SFX Local Collection</source><creator>Kauwe, Grant ; Pareja-Navarro, Kristeen A ; Yao, Lei ; Chen, Jackson H ; Wong, Ivy ; Saloner, Rowan ; Cifuentes, Helen ; Nana, Alissa L ; Shah, Samah ; Li, Yaqiao ; Le, David ; Spina, Salvatore ; Grinberg, Lea T ; Seeley, William W ; Kramer, Joel H ; Sacktor, Todd C ; Schilling, Birgit ; Gan, Li ; Casaletto, Kaitlin B ; Tracy, Tara E</creator><creatorcontrib>Kauwe, Grant ; Pareja-Navarro, Kristeen A ; Yao, Lei ; Chen, Jackson H ; Wong, Ivy ; Saloner, Rowan ; Cifuentes, Helen ; Nana, Alissa L ; Shah, Samah ; Li, Yaqiao ; Le, David ; Spina, Salvatore ; Grinberg, Lea T ; Seeley, William W ; Kramer, Joel H ; Sacktor, Todd C ; Schilling, Birgit ; Gan, Li ; Casaletto, Kaitlin B ; Tracy, Tara E</creatorcontrib><description>Synaptic plasticity is obstructed by pathogenic tau in the brain, representing a key mechanism that underlies memory loss in Alzheimer's disease (AD) and related tauopathies. Here, we found that reduced levels of the memory-associated protein KIdney/BRAin (KIBRA) in the brain and increased KIBRA protein levels in cerebrospinal fluid are associated with cognitive impairment and pathological tau levels in disease. We next defined a mechanism for plasticity repair in vulnerable neurons using the C-terminus of the KIBRA protein (CT-KIBRA). We showed that CT-KIBRA restored plasticity and memory in transgenic mice expressing pathogenic human tau; however, CT-KIBRA did not alter tau levels or prevent tau-induced synapse loss. Instead, we found that CT-KIBRA stabilized the protein kinase Mζ (PKMζ) to maintain synaptic plasticity and memory despite tau-mediated pathogenesis. Thus, our results distinguished KIBRA both as a biomarker of synapse dysfunction and as the foundation for a synapse repair mechanism to reverse cognitive impairment in tauopathy.</description><identifier>ISSN: 1558-8238</identifier><identifier>ISSN: 0021-9738</identifier><identifier>EISSN: 1558-8238</identifier><identifier>DOI: 10.1172/JCI169064</identifier><identifier>PMID: 38299587</identifier><language>eng</language><publisher>United States: American Society for Clinical Investigation</publisher><subject>Advertising executives ; Alzheimer Disease - pathology ; Alzheimer's disease ; Animals ; Biomarkers ; Brain ; Brain - metabolism ; C-Terminus ; Care and treatment ; Causes of ; Cerebrospinal fluid ; Cognition & reasoning ; Cognitive ability ; Complications and side effects ; Development and progression ; Disease Models, Animal ; Genetic engineering ; Health aspects ; Humans ; Immunological memory ; Kidney - metabolism ; Kinases ; Memory ; Memory Disorders - genetics ; Memory Disorders - metabolism ; Memory, Disorders of ; Mice ; Mice, Transgenic ; Neurodegenerative diseases ; Neuronal Plasticity ; Neurons ; Neuroplasticity ; Pathology ; Physiological aspects ; Protein kinases ; Recombinant proteins ; Resilience, Psychological ; Synapses ; Synaptic plasticity ; Tau protein ; Tau proteins ; tau Proteins - genetics ; tau Proteins - metabolism ; Tauopathies - genetics ; Tauopathies - metabolism ; Tauopathies - pathology ; Transgenic mice</subject><ispartof>The Journal of clinical investigation, 2024-02, Vol.134 (3), p.1-18</ispartof><rights>COPYRIGHT 2024 American Society for Clinical Investigation</rights><rights>Copyright American Society for Clinical Investigation Feb 2024</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c5033-430a6addccf067f76648a8eac13064a011a8b2fe71672b4486729ff099c007d83</citedby><cites>FETCH-LOGICAL-c5033-430a6addccf067f76648a8eac13064a011a8b2fe71672b4486729ff099c007d83</cites><orcidid>0000-0003-3570-9143 ; 0000-0002-6809-0618</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27923,27924</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/38299587$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kauwe, Grant</creatorcontrib><creatorcontrib>Pareja-Navarro, Kristeen A</creatorcontrib><creatorcontrib>Yao, Lei</creatorcontrib><creatorcontrib>Chen, Jackson H</creatorcontrib><creatorcontrib>Wong, Ivy</creatorcontrib><creatorcontrib>Saloner, Rowan</creatorcontrib><creatorcontrib>Cifuentes, Helen</creatorcontrib><creatorcontrib>Nana, Alissa L</creatorcontrib><creatorcontrib>Shah, Samah</creatorcontrib><creatorcontrib>Li, Yaqiao</creatorcontrib><creatorcontrib>Le, David</creatorcontrib><creatorcontrib>Spina, Salvatore</creatorcontrib><creatorcontrib>Grinberg, Lea T</creatorcontrib><creatorcontrib>Seeley, William W</creatorcontrib><creatorcontrib>Kramer, Joel H</creatorcontrib><creatorcontrib>Sacktor, Todd C</creatorcontrib><creatorcontrib>Schilling, Birgit</creatorcontrib><creatorcontrib>Gan, Li</creatorcontrib><creatorcontrib>Casaletto, Kaitlin B</creatorcontrib><creatorcontrib>Tracy, Tara E</creatorcontrib><title>KIBRA repairs synaptic plasticity and promotes resilience to tauopathy-related memory loss</title><title>The Journal of clinical investigation</title><addtitle>J Clin Invest</addtitle><description>Synaptic plasticity is obstructed by pathogenic tau in the brain, representing a key mechanism that underlies memory loss in Alzheimer's disease (AD) and related tauopathies. Here, we found that reduced levels of the memory-associated protein KIdney/BRAin (KIBRA) in the brain and increased KIBRA protein levels in cerebrospinal fluid are associated with cognitive impairment and pathological tau levels in disease. We next defined a mechanism for plasticity repair in vulnerable neurons using the C-terminus of the KIBRA protein (CT-KIBRA). We showed that CT-KIBRA restored plasticity and memory in transgenic mice expressing pathogenic human tau; however, CT-KIBRA did not alter tau levels or prevent tau-induced synapse loss. Instead, we found that CT-KIBRA stabilized the protein kinase Mζ (PKMζ) to maintain synaptic plasticity and memory despite tau-mediated pathogenesis. Thus, our results distinguished KIBRA both as a biomarker of synapse dysfunction and as the foundation for a synapse repair mechanism to reverse cognitive impairment in tauopathy.</description><subject>Advertising executives</subject><subject>Alzheimer Disease - pathology</subject><subject>Alzheimer's disease</subject><subject>Animals</subject><subject>Biomarkers</subject><subject>Brain</subject><subject>Brain - metabolism</subject><subject>C-Terminus</subject><subject>Care and treatment</subject><subject>Causes of</subject><subject>Cerebrospinal fluid</subject><subject>Cognition & reasoning</subject><subject>Cognitive ability</subject><subject>Complications and side effects</subject><subject>Development and progression</subject><subject>Disease Models, Animal</subject><subject>Genetic engineering</subject><subject>Health aspects</subject><subject>Humans</subject><subject>Immunological memory</subject><subject>Kidney - metabolism</subject><subject>Kinases</subject><subject>Memory</subject><subject>Memory Disorders - genetics</subject><subject>Memory Disorders - metabolism</subject><subject>Memory, Disorders of</subject><subject>Mice</subject><subject>Mice, Transgenic</subject><subject>Neurodegenerative diseases</subject><subject>Neuronal Plasticity</subject><subject>Neurons</subject><subject>Neuroplasticity</subject><subject>Pathology</subject><subject>Physiological aspects</subject><subject>Protein kinases</subject><subject>Recombinant proteins</subject><subject>Resilience, Psychological</subject><subject>Synapses</subject><subject>Synaptic plasticity</subject><subject>Tau protein</subject><subject>Tau proteins</subject><subject>tau Proteins - genetics</subject><subject>tau Proteins - metabolism</subject><subject>Tauopathies - genetics</subject><subject>Tauopathies - metabolism</subject><subject>Tauopathies - pathology</subject><subject>Transgenic mice</subject><issn>1558-8238</issn><issn>0021-9738</issn><issn>1558-8238</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2024</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><recordid>eNqN0ktv1DAQAGALUdFSOPAHkCUkRA8pduLEznFZ8dhSqVJ5HLhEs85k15UTB9uRyL_Hq5bSRXtAPoxlfR6Nx0PIC87OOZf524vlilc1q8QjcsLLUmUqL9TjB_tj8jSEG8a4EKV4Qo4Lldd1qeQJ-fF59e56QT2OYHygYR5gjEbT0UJI0cSZwtDS0bveRQwJBmMNDhppdDTC5EaI2znzaCFiS3vsnZ-pdSE8I0cd2IDP7-Ip-fbh_dflp-zy6uNqubjMdMmKIhMFgwraVuuOVbKTVSUUKATNi_QiYJyDWucdSl7JfC2ESqHuOlbXmjHZquKUvLnNm4r8OWGITW-CRmthQDeFJq9zntokuUj01T_0xk1-SNXtVM1FWeXlX7UBi40ZOhc96F3SZiFVmTOZSksqO6A2OKAH6wbsTDre8-cHfFot9kYfvHC2dyGZiL_iBqYQmtWX6_-3V9_37esHdotg4zY4O0XjhnAwqfbpOz12zehND35uOGt2g9fcD16yL-86O617bO_ln0krfgNX4Mz4</recordid><startdate>20240201</startdate><enddate>20240201</enddate><creator>Kauwe, Grant</creator><creator>Pareja-Navarro, Kristeen A</creator><creator>Yao, Lei</creator><creator>Chen, Jackson H</creator><creator>Wong, Ivy</creator><creator>Saloner, Rowan</creator><creator>Cifuentes, Helen</creator><creator>Nana, Alissa L</creator><creator>Shah, Samah</creator><creator>Li, Yaqiao</creator><creator>Le, David</creator><creator>Spina, Salvatore</creator><creator>Grinberg, Lea T</creator><creator>Seeley, William W</creator><creator>Kramer, Joel H</creator><creator>Sacktor, Todd C</creator><creator>Schilling, Birgit</creator><creator>Gan, Li</creator><creator>Casaletto, Kaitlin B</creator><creator>Tracy, Tara E</creator><general>American Society for Clinical Investigation</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>IOV</scope><scope>ISR</scope><scope>3V.</scope><scope>7RV</scope><scope>7X7</scope><scope>7XB</scope><scope>88A</scope><scope>88E</scope><scope>8AO</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BEC</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB0</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M7P</scope><scope>NAPCQ</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>S0X</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0003-3570-9143</orcidid><orcidid>https://orcid.org/0000-0002-6809-0618</orcidid></search><sort><creationdate>20240201</creationdate><title>KIBRA repairs synaptic plasticity and promotes resilience to tauopathy-related memory loss</title><author>Kauwe, Grant ; Pareja-Navarro, Kristeen A ; Yao, Lei ; Chen, Jackson H ; Wong, Ivy ; Saloner, Rowan ; Cifuentes, Helen ; Nana, Alissa L ; Shah, Samah ; Li, Yaqiao ; Le, David ; Spina, Salvatore ; Grinberg, Lea T ; Seeley, William W ; Kramer, Joel H ; Sacktor, Todd C ; Schilling, Birgit ; Gan, Li ; Casaletto, Kaitlin B ; Tracy, Tara E</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c5033-430a6addccf067f76648a8eac13064a011a8b2fe71672b4486729ff099c007d83</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2024</creationdate><topic>Advertising executives</topic><topic>Alzheimer Disease - pathology</topic><topic>Alzheimer's disease</topic><topic>Animals</topic><topic>Biomarkers</topic><topic>Brain</topic><topic>Brain - metabolism</topic><topic>C-Terminus</topic><topic>Care and treatment</topic><topic>Causes of</topic><topic>Cerebrospinal fluid</topic><topic>Cognition & reasoning</topic><topic>Cognitive ability</topic><topic>Complications and side effects</topic><topic>Development and progression</topic><topic>Disease Models, Animal</topic><topic>Genetic engineering</topic><topic>Health aspects</topic><topic>Humans</topic><topic>Immunological memory</topic><topic>Kidney - metabolism</topic><topic>Kinases</topic><topic>Memory</topic><topic>Memory Disorders - genetics</topic><topic>Memory Disorders - metabolism</topic><topic>Memory, Disorders of</topic><topic>Mice</topic><topic>Mice, Transgenic</topic><topic>Neurodegenerative diseases</topic><topic>Neuronal Plasticity</topic><topic>Neurons</topic><topic>Neuroplasticity</topic><topic>Pathology</topic><topic>Physiological aspects</topic><topic>Protein kinases</topic><topic>Recombinant proteins</topic><topic>Resilience, Psychological</topic><topic>Synapses</topic><topic>Synaptic plasticity</topic><topic>Tau protein</topic><topic>Tau proteins</topic><topic>tau Proteins - genetics</topic><topic>tau Proteins - metabolism</topic><topic>Tauopathies - genetics</topic><topic>Tauopathies - metabolism</topic><topic>Tauopathies - pathology</topic><topic>Transgenic mice</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Kauwe, Grant</creatorcontrib><creatorcontrib>Pareja-Navarro, Kristeen A</creatorcontrib><creatorcontrib>Yao, Lei</creatorcontrib><creatorcontrib>Chen, Jackson H</creatorcontrib><creatorcontrib>Wong, Ivy</creatorcontrib><creatorcontrib>Saloner, Rowan</creatorcontrib><creatorcontrib>Cifuentes, Helen</creatorcontrib><creatorcontrib>Nana, Alissa L</creatorcontrib><creatorcontrib>Shah, Samah</creatorcontrib><creatorcontrib>Li, Yaqiao</creatorcontrib><creatorcontrib>Le, David</creatorcontrib><creatorcontrib>Spina, Salvatore</creatorcontrib><creatorcontrib>Grinberg, Lea T</creatorcontrib><creatorcontrib>Seeley, William W</creatorcontrib><creatorcontrib>Kramer, Joel H</creatorcontrib><creatorcontrib>Sacktor, Todd C</creatorcontrib><creatorcontrib>Schilling, Birgit</creatorcontrib><creatorcontrib>Gan, Li</creatorcontrib><creatorcontrib>Casaletto, Kaitlin B</creatorcontrib><creatorcontrib>Tracy, Tara E</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Gale In Context: Opposing Viewpoints</collection><collection>Gale In Context: Science</collection><collection>ProQuest Central (Corporate)</collection><collection>Nursing & Allied Health Database</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Biology Database (Alumni Edition)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>eLibrary</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Biological Science Database</collection><collection>Nursing & Allied Health Premium</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>SIRS Editorial</collection><collection>MEDLINE - Academic</collection><jtitle>The Journal of clinical investigation</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Kauwe, Grant</au><au>Pareja-Navarro, Kristeen A</au><au>Yao, Lei</au><au>Chen, Jackson H</au><au>Wong, Ivy</au><au>Saloner, Rowan</au><au>Cifuentes, Helen</au><au>Nana, Alissa L</au><au>Shah, Samah</au><au>Li, Yaqiao</au><au>Le, David</au><au>Spina, Salvatore</au><au>Grinberg, Lea T</au><au>Seeley, William W</au><au>Kramer, Joel H</au><au>Sacktor, Todd C</au><au>Schilling, Birgit</au><au>Gan, Li</au><au>Casaletto, Kaitlin B</au><au>Tracy, Tara E</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>KIBRA repairs synaptic plasticity and promotes resilience to tauopathy-related memory loss</atitle><jtitle>The Journal of clinical investigation</jtitle><addtitle>J Clin Invest</addtitle><date>2024-02-01</date><risdate>2024</risdate><volume>134</volume><issue>3</issue><spage>1</spage><epage>18</epage><pages>1-18</pages><issn>1558-8238</issn><issn>0021-9738</issn><eissn>1558-8238</eissn><abstract>Synaptic plasticity is obstructed by pathogenic tau in the brain, representing a key mechanism that underlies memory loss in Alzheimer's disease (AD) and related tauopathies. Here, we found that reduced levels of the memory-associated protein KIdney/BRAin (KIBRA) in the brain and increased KIBRA protein levels in cerebrospinal fluid are associated with cognitive impairment and pathological tau levels in disease. We next defined a mechanism for plasticity repair in vulnerable neurons using the C-terminus of the KIBRA protein (CT-KIBRA). We showed that CT-KIBRA restored plasticity and memory in transgenic mice expressing pathogenic human tau; however, CT-KIBRA did not alter tau levels or prevent tau-induced synapse loss. Instead, we found that CT-KIBRA stabilized the protein kinase Mζ (PKMζ) to maintain synaptic plasticity and memory despite tau-mediated pathogenesis. Thus, our results distinguished KIBRA both as a biomarker of synapse dysfunction and as the foundation for a synapse repair mechanism to reverse cognitive impairment in tauopathy.</abstract><cop>United States</cop><pub>American Society for Clinical Investigation</pub><pmid>38299587</pmid><doi>10.1172/JCI169064</doi><tpages>18</tpages><orcidid>https://orcid.org/0000-0003-3570-9143</orcidid><orcidid>https://orcid.org/0000-0002-6809-0618</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1558-8238 |
| ispartof | The Journal of clinical investigation, 2024-02, Vol.134 (3), p.1-18 |
| issn | 1558-8238 0021-9738 1558-8238 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_2921117714 |
| source | MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central; Alma/SFX Local Collection |
| subjects | Advertising executives Alzheimer Disease - pathology Alzheimer's disease Animals Biomarkers Brain Brain - metabolism C-Terminus Care and treatment Causes of Cerebrospinal fluid Cognition & reasoning Cognitive ability Complications and side effects Development and progression Disease Models, Animal Genetic engineering Health aspects Humans Immunological memory Kidney - metabolism Kinases Memory Memory Disorders - genetics Memory Disorders - metabolism Memory, Disorders of Mice Mice, Transgenic Neurodegenerative diseases Neuronal Plasticity Neurons Neuroplasticity Pathology Physiological aspects Protein kinases Recombinant proteins Resilience, Psychological Synapses Synaptic plasticity Tau protein Tau proteins tau Proteins - genetics tau Proteins - metabolism Tauopathies - genetics Tauopathies - metabolism Tauopathies - pathology Transgenic mice |
| title | KIBRA repairs synaptic plasticity and promotes resilience to tauopathy-related memory loss |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-08T19%3A31%3A04IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_proqu&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=KIBRA%20repairs%20synaptic%20plasticity%20and%20promotes%20resilience%20to%20tauopathy-related%20memory%20loss&rft.jtitle=The%20Journal%20of%20clinical%20investigation&rft.au=Kauwe,%20Grant&rft.date=2024-02-01&rft.volume=134&rft.issue=3&rft.spage=1&rft.epage=18&rft.pages=1-18&rft.issn=1558-8238&rft.eissn=1558-8238&rft_id=info:doi/10.1172/JCI169064&rft_dat=%3Cgale_proqu%3EA785207130%3C/gale_proqu%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2929145625&rft_id=info:pmid/38299587&rft_galeid=A785207130&rfr_iscdi=true |