Increased expression of three-repeat isoforms of tau contributes to tau pathology in a rat model of chronic type 2 diabetes
The imbalance between three-repeat (3R) and four-repeat (4R) tau isoforms produced by the alternative splicing of tau exon 10 leads to neuronal instability and eventual neurodegeneration in tauopathy. However, the role of altered 3R/4R tau ratio in Alzheimer's disease (AD) remains controversial...
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| Veröffentlicht in: | Experimental neurology 2011-04, Vol.228 (2), p.232-241 |
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| creator | Jung, Hyun Jung Park, Seok Soon Mok, Ji Oh Lee, Tae Kyeong Park, Choon Sik Park, Sun Ah |
| description | The imbalance between three-repeat (3R) and four-repeat (4R) tau isoforms produced by the alternative splicing of tau exon 10 leads to neuronal instability and eventual neurodegeneration in tauopathy. However, the role of altered 3R/4R tau ratio in Alzheimer's disease (AD) remains controversial. It has been shown that the expression of 3R tau is modulated by peptide amyloid β (Aβ) and that 3R tau levels increase with the progression of AD. The incidence of AD increases in patients with type 2 diabetes mellitus (T2DM), and the comorbidity of these disorders is closely associated with both aging and disease duration. To investigate whether changes in 3R and 4R tau isoforms are involved in AD pathology pertaining to age-related T2DM, the expression of tau isoforms and their relationship with AD-like tau pathology were examined in a spontaneous T2DM model using aged Otsuka Long–Evans Tokushima Fatty (OLETF) rats with obesity. An AD-like pathology consisting of increased aggregates in the neuronal cytoplasm and a loss of synaptic proteins was observed in these rats. The aggregates were reactive with a 3R tau-specific, but not 4R tau-specific, antibody. In contrast to 4R tau, the level of 3R tau profoundly increased and the proteins were prone to taking toxic phosphorylated and truncated forms. Taken together, these findings suggest that increased 3R tau may contribute to AD-like tau pathology in a chronic T2DM model. Thus, the restoration of normal 3R tau expression should be considered as an important therapeutic strategy in the treatment of AD.
► Impaired insulin signaling and decreased synaptic protein in OLETF rats. ► Markedly increased 3R tau isoforms form aggregates in neurons of OLETF rats. ► Increased 3R tau mRNA is accompanied by increased splicing factors, SRp55. ► Increased Tau phosphorylation at Thr212 in the soluble fraction of brain. ► 3R tau not 4R tau contribute to increased phosphorylation of tau. |
| doi_str_mv | 10.1016/j.expneurol.2011.01.012 |
| format | Article |
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► Impaired insulin signaling and decreased synaptic protein in OLETF rats. ► Markedly increased 3R tau isoforms form aggregates in neurons of OLETF rats. ► Increased 3R tau mRNA is accompanied by increased splicing factors, SRp55. ► Increased Tau phosphorylation at Thr212 in the soluble fraction of brain. ► 3R tau not 4R tau contribute to increased phosphorylation of tau.</description><identifier>ISSN: 0014-4886</identifier><identifier>EISSN: 1090-2430</identifier><identifier>DOI: 10.1016/j.expneurol.2011.01.012</identifier><identifier>PMID: 21281635</identifier><identifier>CODEN: EXNEAC</identifier><language>eng</language><publisher>Amsterdam: Elsevier Inc</publisher><subject>Age ; Aging ; Alternative splicing ; Alzheimer Disease - complications ; Alzheimer Disease - metabolism ; Alzheimer's disease ; Animal models ; Animals ; Antibodies ; beta -Amyloid ; Biological and medical sciences ; Chronic Disease ; Cytoplasm ; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases ; Diabetes mellitus ; Diabetes Mellitus, Type 2 - complications ; Diabetes Mellitus, Type 2 - metabolism ; Disease Models, Animal ; Exons ; Isoform ; Medical sciences ; Neurodegenerative diseases ; Neurology ; Obesity ; Protein Isoforms - biosynthesis ; Protein Isoforms - chemistry ; Protein Isoforms - genetics ; Rats ; Rats, Inbred OLETF ; Repetitive Sequences, Amino Acid ; Splicing ; Tau ; Tau protein ; tau Proteins - biosynthesis ; tau Proteins - chemistry ; tau Proteins - genetics ; Tauopathies - complications ; Tauopathies - metabolism ; Type 2 diabetes</subject><ispartof>Experimental neurology, 2011-04, Vol.228 (2), p.232-241</ispartof><rights>2011 Elsevier Inc.</rights><rights>2015 INIST-CNRS</rights><rights>Copyright © 2011 Elsevier Inc. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c498t-b02e77eee62036941a79090bf62f56486b3a0e6fd8e228a36d7ca39cdf941b1c3</citedby><cites>FETCH-LOGICAL-c498t-b02e77eee62036941a79090bf62f56486b3a0e6fd8e228a36d7ca39cdf941b1c3</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.2011.01.012$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>315,781,785,3551,27929,27930,46000</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=24029964$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/21281635$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Jung, Hyun Jung</creatorcontrib><creatorcontrib>Park, Seok Soon</creatorcontrib><creatorcontrib>Mok, Ji Oh</creatorcontrib><creatorcontrib>Lee, Tae Kyeong</creatorcontrib><creatorcontrib>Park, Choon Sik</creatorcontrib><creatorcontrib>Park, Sun Ah</creatorcontrib><title>Increased expression of three-repeat isoforms of tau contributes to tau pathology in a rat model of chronic type 2 diabetes</title><title>Experimental neurology</title><addtitle>Exp Neurol</addtitle><description>The imbalance between three-repeat (3R) and four-repeat (4R) tau isoforms produced by the alternative splicing of tau exon 10 leads to neuronal instability and eventual neurodegeneration in tauopathy. However, the role of altered 3R/4R tau ratio in Alzheimer's disease (AD) remains controversial. It has been shown that the expression of 3R tau is modulated by peptide amyloid β (Aβ) and that 3R tau levels increase with the progression of AD. The incidence of AD increases in patients with type 2 diabetes mellitus (T2DM), and the comorbidity of these disorders is closely associated with both aging and disease duration. To investigate whether changes in 3R and 4R tau isoforms are involved in AD pathology pertaining to age-related T2DM, the expression of tau isoforms and their relationship with AD-like tau pathology were examined in a spontaneous T2DM model using aged Otsuka Long–Evans Tokushima Fatty (OLETF) rats with obesity. An AD-like pathology consisting of increased aggregates in the neuronal cytoplasm and a loss of synaptic proteins was observed in these rats. The aggregates were reactive with a 3R tau-specific, but not 4R tau-specific, antibody. In contrast to 4R tau, the level of 3R tau profoundly increased and the proteins were prone to taking toxic phosphorylated and truncated forms. Taken together, these findings suggest that increased 3R tau may contribute to AD-like tau pathology in a chronic T2DM model. Thus, the restoration of normal 3R tau expression should be considered as an important therapeutic strategy in the treatment of AD.
► Impaired insulin signaling and decreased synaptic protein in OLETF rats. ► Markedly increased 3R tau isoforms form aggregates in neurons of OLETF rats. ► Increased 3R tau mRNA is accompanied by increased splicing factors, SRp55. ► Increased Tau phosphorylation at Thr212 in the soluble fraction of brain. ► 3R tau not 4R tau contribute to increased phosphorylation of tau.</description><subject>Age</subject><subject>Aging</subject><subject>Alternative splicing</subject><subject>Alzheimer Disease - complications</subject><subject>Alzheimer Disease - metabolism</subject><subject>Alzheimer's disease</subject><subject>Animal models</subject><subject>Animals</subject><subject>Antibodies</subject><subject>beta -Amyloid</subject><subject>Biological and medical sciences</subject><subject>Chronic Disease</subject><subject>Cytoplasm</subject><subject>Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases</subject><subject>Diabetes mellitus</subject><subject>Diabetes Mellitus, Type 2 - complications</subject><subject>Diabetes Mellitus, Type 2 - metabolism</subject><subject>Disease Models, Animal</subject><subject>Exons</subject><subject>Isoform</subject><subject>Medical sciences</subject><subject>Neurodegenerative diseases</subject><subject>Neurology</subject><subject>Obesity</subject><subject>Protein Isoforms - biosynthesis</subject><subject>Protein Isoforms - chemistry</subject><subject>Protein Isoforms - genetics</subject><subject>Rats</subject><subject>Rats, Inbred OLETF</subject><subject>Repetitive Sequences, Amino Acid</subject><subject>Splicing</subject><subject>Tau</subject><subject>Tau protein</subject><subject>tau Proteins - biosynthesis</subject><subject>tau Proteins - chemistry</subject><subject>tau Proteins - genetics</subject><subject>Tauopathies - complications</subject><subject>Tauopathies - metabolism</subject><subject>Type 2 diabetes</subject><issn>0014-4886</issn><issn>1090-2430</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2011</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkE1v3CAQhlHVqtkm-Qstl6onbwATbI5R1I9IkXpJzwjD0GVlgwu46ip_vji7SY-VRkJinndgHoQ-ULKlhIqr_Rb-zAGWFMctI5RuyVrsFdpQIknDeEteow0hlDe878UZepfznhAiOeveojNGWU9Fe71Bj3fBJNAZLK4TE-TsY8DR4bJLAE2CGXTBPkcX05SfGnrBJoaS_LAUyLjEp6tZl10c488D9gFrnGpqihbGNWJ2KQZvcDnMgBm2Xg9QoxfojdNjhsvTeY5-fPn8cPutuf_-9e725r4xXPalGQiDrgMAwUgrJKe6k3XJwQnmrgXvxdBqAsLZHhjrdStsZ3QrjXWVHahpz9Gn49w5xV8L5KImnw2Mow4Ql6x6wbqeSyor2R1Jk2LOCZyak590OihK1Cpe7dWLeLWKV2QtVpPvT28swwT2JfdsugIfT4DORo8u6WB8_sdxwqQUvHI3Rw6qkd8eksrGQzBgfQJTlI3-v5_5C-Mzp6I</recordid><startdate>20110401</startdate><enddate>20110401</enddate><creator>Jung, Hyun Jung</creator><creator>Park, Seok Soon</creator><creator>Mok, Ji Oh</creator><creator>Lee, Tae Kyeong</creator><creator>Park, Choon Sik</creator><creator>Park, Sun Ah</creator><general>Elsevier Inc</general><general>Elsevier</general><scope>IQODW</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>7TK</scope><scope>7U7</scope><scope>C1K</scope></search><sort><creationdate>20110401</creationdate><title>Increased expression of three-repeat isoforms of tau contributes to tau pathology in a rat model of chronic type 2 diabetes</title><author>Jung, Hyun Jung ; Park, Seok Soon ; Mok, Ji Oh ; Lee, Tae Kyeong ; Park, Choon Sik ; Park, Sun Ah</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c498t-b02e77eee62036941a79090bf62f56486b3a0e6fd8e228a36d7ca39cdf941b1c3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2011</creationdate><topic>Age</topic><topic>Aging</topic><topic>Alternative splicing</topic><topic>Alzheimer Disease - complications</topic><topic>Alzheimer Disease - metabolism</topic><topic>Alzheimer's disease</topic><topic>Animal models</topic><topic>Animals</topic><topic>Antibodies</topic><topic>beta -Amyloid</topic><topic>Biological and medical sciences</topic><topic>Chronic Disease</topic><topic>Cytoplasm</topic><topic>Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases</topic><topic>Diabetes mellitus</topic><topic>Diabetes Mellitus, Type 2 - complications</topic><topic>Diabetes Mellitus, Type 2 - metabolism</topic><topic>Disease Models, Animal</topic><topic>Exons</topic><topic>Isoform</topic><topic>Medical sciences</topic><topic>Neurodegenerative diseases</topic><topic>Neurology</topic><topic>Obesity</topic><topic>Protein Isoforms - biosynthesis</topic><topic>Protein Isoforms - chemistry</topic><topic>Protein Isoforms - genetics</topic><topic>Rats</topic><topic>Rats, Inbred OLETF</topic><topic>Repetitive Sequences, Amino Acid</topic><topic>Splicing</topic><topic>Tau</topic><topic>Tau protein</topic><topic>tau Proteins - biosynthesis</topic><topic>tau Proteins - chemistry</topic><topic>tau Proteins - genetics</topic><topic>Tauopathies - complications</topic><topic>Tauopathies - metabolism</topic><topic>Type 2 diabetes</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Jung, Hyun Jung</creatorcontrib><creatorcontrib>Park, Seok Soon</creatorcontrib><creatorcontrib>Mok, Ji Oh</creatorcontrib><creatorcontrib>Lee, Tae Kyeong</creatorcontrib><creatorcontrib>Park, Choon Sik</creatorcontrib><creatorcontrib>Park, Sun Ah</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Neurosciences Abstracts</collection><collection>Toxicology Abstracts</collection><collection>Environmental Sciences and Pollution Management</collection><jtitle>Experimental neurology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Jung, Hyun Jung</au><au>Park, Seok Soon</au><au>Mok, Ji Oh</au><au>Lee, Tae Kyeong</au><au>Park, Choon Sik</au><au>Park, Sun Ah</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Increased expression of three-repeat isoforms of tau contributes to tau pathology in a rat model of chronic type 2 diabetes</atitle><jtitle>Experimental neurology</jtitle><addtitle>Exp Neurol</addtitle><date>2011-04-01</date><risdate>2011</risdate><volume>228</volume><issue>2</issue><spage>232</spage><epage>241</epage><pages>232-241</pages><issn>0014-4886</issn><eissn>1090-2430</eissn><coden>EXNEAC</coden><abstract>The imbalance between three-repeat (3R) and four-repeat (4R) tau isoforms produced by the alternative splicing of tau exon 10 leads to neuronal instability and eventual neurodegeneration in tauopathy. However, the role of altered 3R/4R tau ratio in Alzheimer's disease (AD) remains controversial. It has been shown that the expression of 3R tau is modulated by peptide amyloid β (Aβ) and that 3R tau levels increase with the progression of AD. The incidence of AD increases in patients with type 2 diabetes mellitus (T2DM), and the comorbidity of these disorders is closely associated with both aging and disease duration. To investigate whether changes in 3R and 4R tau isoforms are involved in AD pathology pertaining to age-related T2DM, the expression of tau isoforms and their relationship with AD-like tau pathology were examined in a spontaneous T2DM model using aged Otsuka Long–Evans Tokushima Fatty (OLETF) rats with obesity. An AD-like pathology consisting of increased aggregates in the neuronal cytoplasm and a loss of synaptic proteins was observed in these rats. The aggregates were reactive with a 3R tau-specific, but not 4R tau-specific, antibody. In contrast to 4R tau, the level of 3R tau profoundly increased and the proteins were prone to taking toxic phosphorylated and truncated forms. Taken together, these findings suggest that increased 3R tau may contribute to AD-like tau pathology in a chronic T2DM model. Thus, the restoration of normal 3R tau expression should be considered as an important therapeutic strategy in the treatment of AD.
► Impaired insulin signaling and decreased synaptic protein in OLETF rats. ► Markedly increased 3R tau isoforms form aggregates in neurons of OLETF rats. ► Increased 3R tau mRNA is accompanied by increased splicing factors, SRp55. ► Increased Tau phosphorylation at Thr212 in the soluble fraction of brain. ► 3R tau not 4R tau contribute to increased phosphorylation of tau.</abstract><cop>Amsterdam</cop><pub>Elsevier Inc</pub><pmid>21281635</pmid><doi>10.1016/j.expneurol.2011.01.012</doi><tpages>10</tpages></addata></record> |
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| subjects | Age Aging Alternative splicing Alzheimer Disease - complications Alzheimer Disease - metabolism Alzheimer's disease Animal models Animals Antibodies beta -Amyloid Biological and medical sciences Chronic Disease Cytoplasm Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases Diabetes mellitus Diabetes Mellitus, Type 2 - complications Diabetes Mellitus, Type 2 - metabolism Disease Models, Animal Exons Isoform Medical sciences Neurodegenerative diseases Neurology Obesity Protein Isoforms - biosynthesis Protein Isoforms - chemistry Protein Isoforms - genetics Rats Rats, Inbred OLETF Repetitive Sequences, Amino Acid Splicing Tau Tau protein tau Proteins - biosynthesis tau Proteins - chemistry tau Proteins - genetics Tauopathies - complications Tauopathies - metabolism Type 2 diabetes |
| title | Increased expression of three-repeat isoforms of tau contributes to tau pathology in a rat model of chronic type 2 diabetes |
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