The MAPT H1 haplotype is associated with tangle-predominant dementia
Identifieur interne : 000758 ( Pmc/Checkpoint ); précédent : 000757; suivant : 000759The MAPT H1 haplotype is associated with tangle-predominant dementia
Auteurs : Ismael Santa-Maria ; Aya Haggiagi ; Xinmin Liu ; Jessica Wasserscheid ; Peter T. Nelson ; Ken Dewar ; Lorraine N. Clark ; John F. CrarySource :
- Acta neuropathologica [ 0001-6322 ] ; 2012.
Abstract
Tangle-predominant dementia (TPD) patients exhibit cognitive decline that is clinically similar to early to moderate-stage Alzheimer disease (AD), yet autopsy reveals neurofibrillary tangles in the medial temporal lobe composed of the microtubule-associated protein tau without significant amyloid-beta (Aβ)-positive plaques. We performed a series of neuropathological, biochemical and genetic studies using autopsy brain tissue drawn from a cohort of 34 TPD, 50 AD and 56 control subjects to identify molecular and genetic signatures of this entity. Biochemical analysis demonstrates a similar tau protein isoform composition in TPD and AD, which is compatible with previous histological and ultrastructural studies. Further, biochemical analysis fails to uncover elevation of soluble Aβ in TPD frontal cortex and hippocampus compared to control subjects, demonstrating that non-plaque-associated Aβ is not a contributing factor. Unexpectedly, we also observed high levels of secretory amyloid precursor protein α (sAPPα) in the frontal cortex of some TPD patients compared to AD and control subjects, suggesting differences in APP processing. Finally, we tested whether TPD is associated with changes in the tau gene (
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DOI: 10.1007/s00401-012-1017-1
PubMed: 22802095
PubMed Central: 3608475
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H1 haplotype is associated with tangle-predominant dementia</title>
<author><name sortKey="Santa Maria, Ismael" sort="Santa Maria, Ismael" uniqKey="Santa Maria I" first="Ismael" last="Santa-Maria">Ismael Santa-Maria</name>
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<author><name sortKey="Liu, Xinmin" sort="Liu, Xinmin" uniqKey="Liu X" first="Xinmin" last="Liu">Xinmin Liu</name>
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<author><name sortKey="Wasserscheid, Jessica" sort="Wasserscheid, Jessica" uniqKey="Wasserscheid J" first="Jessica" last="Wasserscheid">Jessica Wasserscheid</name>
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<author><name sortKey="Nelson, Peter T" sort="Nelson, Peter T" uniqKey="Nelson P" first="Peter T." last="Nelson">Peter T. Nelson</name>
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<author><name sortKey="Dewar, Ken" sort="Dewar, Ken" uniqKey="Dewar K" first="Ken" last="Dewar">Ken Dewar</name>
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<author><name sortKey="Clark, Lorraine N" sort="Clark, Lorraine N" uniqKey="Clark L" first="Lorraine N." last="Clark">Lorraine N. Clark</name>
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H1 haplotype is associated with tangle-predominant dementia</title>
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<front><div type="abstract" xml:lang="en"><p id="P1">Tangle-predominant dementia (TPD) patients exhibit cognitive decline that is clinically similar to early to moderate-stage Alzheimer disease (AD), yet autopsy reveals neurofibrillary tangles in the medial temporal lobe composed of the microtubule-associated protein tau without significant amyloid-beta (Aβ)-positive plaques. We performed a series of neuropathological, biochemical and genetic studies using autopsy brain tissue drawn from a cohort of 34 TPD, 50 AD and 56 control subjects to identify molecular and genetic signatures of this entity. Biochemical analysis demonstrates a similar tau protein isoform composition in TPD and AD, which is compatible with previous histological and ultrastructural studies. Further, biochemical analysis fails to uncover elevation of soluble Aβ in TPD frontal cortex and hippocampus compared to control subjects, demonstrating that non-plaque-associated Aβ is not a contributing factor. Unexpectedly, we also observed high levels of secretory amyloid precursor protein α (sAPPα) in the frontal cortex of some TPD patients compared to AD and control subjects, suggesting differences in APP processing. Finally, we tested whether TPD is associated with changes in the tau gene (<italic>MAPT</italic>
). Haplotype analysis demonstrates a strong association between TPD and the <italic>MAPT</italic>
H1 haplotype, a genomic inversion associated with some tauopathies and Parkinson disease (PD), when compared to age-matched control subjects with mild degenerative changes, i.e., successful cerebral aging. Next-generation resequencing of <italic>MAPT</italic>
followed by association analysis shows an association between TPD and two polymorphisms in the <italic>MAPT</italic>
3′ untranslated region (UTR). These results support the hypothesis that haplotype-specific variation in the <italic>MAPT</italic>
3′ UTR underlies an Aβ-independent mechanism for neurodegeneration in TPD.</p>
</div>
</front>
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<pmc article-type="research-article"><pmc-comment>The publisher of this article does not allow downloading of the full text in XML form.</pmc-comment>
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<front><journal-meta><journal-id journal-id-type="nlm-journal-id">0412041</journal-id>
<journal-id journal-id-type="pubmed-jr-id">133</journal-id>
<journal-id journal-id-type="nlm-ta">Acta Neuropathol</journal-id>
<journal-id journal-id-type="iso-abbrev">Acta Neuropathol.</journal-id>
<journal-title-group><journal-title>Acta neuropathologica</journal-title>
</journal-title-group>
<issn pub-type="ppub">0001-6322</issn>
<issn pub-type="epub">1432-0533</issn>
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<article-id pub-id-type="pmc">3608475</article-id>
<article-id pub-id-type="doi">10.1007/s00401-012-1017-1</article-id>
<article-id pub-id-type="manuscript">NIHMS444537</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>Article</subject>
</subj-group>
</article-categories>
<title-group><article-title>The <bold><italic>MAPT</italic>
</bold>
H1 haplotype is associated with tangle-predominant dementia</article-title>
</title-group>
<contrib-group><contrib contrib-type="author"><name><surname>Santa-Maria</surname>
<given-names>Ismael</given-names>
</name>
<aff id="A1">Department of Pathology and Cell Biology, Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, Columbia University, New York 10032, USA</aff>
</contrib>
<contrib contrib-type="author"><name><surname>Haggiagi</surname>
<given-names>Aya</given-names>
</name>
<aff id="A2">Department of Pathology and Cell Biology, Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, Columbia University, New York 10032, USA</aff>
</contrib>
<contrib contrib-type="author"><name><surname>Liu</surname>
<given-names>Xinmin</given-names>
</name>
<aff id="A3">Department of Pathology and Cell Biology, Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, Columbia University, New York 10032, USA</aff>
</contrib>
<contrib contrib-type="author"><name><surname>Wasserscheid</surname>
<given-names>Jessica</given-names>
</name>
<aff id="A4">Department of Human Genetics, McGill University, Montreal, QC H3A 1A4, Canada</aff>
</contrib>
<contrib contrib-type="author"><name><surname>Nelson</surname>
<given-names>Peter T.</given-names>
</name>
<aff id="A5">Division of Neuropathology, Department of Pathology, Sanders-Brown Center on Aging, University of Kentucky, 800 S. Limestone, Lexington, KY 40536, USA</aff>
</contrib>
<contrib contrib-type="author"><name><surname>Dewar</surname>
<given-names>Ken</given-names>
</name>
<aff id="A6">Department of Human Genetics, McGill University, Montreal, QC H3A 1A4, Canada</aff>
</contrib>
<contrib contrib-type="author"><name><surname>Clark</surname>
<given-names>Lorraine N.</given-names>
</name>
<aff id="A7">Department of Pathology and Cell Biology, Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, Columbia University, New York 10032, USA</aff>
</contrib>
<contrib contrib-type="author" corresp="yes"><name><surname>Crary</surname>
<given-names>John F.</given-names>
</name>
<aff id="A8">Department of Pathology and Cell Biology, Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, Columbia University, New York 10032, USA, Department of Pathology and Cell Biology, Columbia University Medical Center, 630 168th Street PH15-124, New York, NY 10032, USA</aff>
<email>jc2892@columbia.edu</email>
</contrib>
</contrib-group>
<pub-date pub-type="nihms-submitted"><day>11</day>
<month>3</month>
<year>2013</year>
</pub-date>
<pub-date pub-type="epub"><day>17</day>
<month>7</month>
<year>2012</year>
</pub-date>
<pub-date pub-type="ppub"><month>11</month>
<year>2012</year>
</pub-date>
<pub-date pub-type="pmc-release"><day>01</day>
<month>11</month>
<year>2013</year>
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<volume>124</volume>
<issue>5</issue>
<fpage>693</fpage>
<lpage>704</lpage>
<permissions><copyright-statement>© Springer-Verlag 2012</copyright-statement>
<copyright-year>2012</copyright-year>
</permissions>
<abstract><p id="P1">Tangle-predominant dementia (TPD) patients exhibit cognitive decline that is clinically similar to early to moderate-stage Alzheimer disease (AD), yet autopsy reveals neurofibrillary tangles in the medial temporal lobe composed of the microtubule-associated protein tau without significant amyloid-beta (Aβ)-positive plaques. We performed a series of neuropathological, biochemical and genetic studies using autopsy brain tissue drawn from a cohort of 34 TPD, 50 AD and 56 control subjects to identify molecular and genetic signatures of this entity. Biochemical analysis demonstrates a similar tau protein isoform composition in TPD and AD, which is compatible with previous histological and ultrastructural studies. Further, biochemical analysis fails to uncover elevation of soluble Aβ in TPD frontal cortex and hippocampus compared to control subjects, demonstrating that non-plaque-associated Aβ is not a contributing factor. Unexpectedly, we also observed high levels of secretory amyloid precursor protein α (sAPPα) in the frontal cortex of some TPD patients compared to AD and control subjects, suggesting differences in APP processing. Finally, we tested whether TPD is associated with changes in the tau gene (<italic>MAPT</italic>
). Haplotype analysis demonstrates a strong association between TPD and the <italic>MAPT</italic>
H1 haplotype, a genomic inversion associated with some tauopathies and Parkinson disease (PD), when compared to age-matched control subjects with mild degenerative changes, i.e., successful cerebral aging. Next-generation resequencing of <italic>MAPT</italic>
followed by association analysis shows an association between TPD and two polymorphisms in the <italic>MAPT</italic>
3′ untranslated region (UTR). These results support the hypothesis that haplotype-specific variation in the <italic>MAPT</italic>
3′ UTR underlies an Aβ-independent mechanism for neurodegeneration in TPD.</p>
</abstract>
<kwd-group><kwd>Dementia</kwd>
<kwd>Neurofibrillary tangle</kwd>
<kwd>Tau</kwd>
<kwd>Amyloid</kwd>
<kwd>MAPT</kwd>
<kwd>3′ Untranslated region</kwd>
<kwd>Aging</kwd>
<kwd>Alzheimer’s disease</kwd>
<kwd>sAPPα</kwd>
</kwd-group>
<funding-group><award-group><funding-source country="United States">National Institute on Aging : NIA</funding-source>
<award-id>R01 AG037212 || AG</award-id>
</award-group>
<award-group><funding-source country="United States">National Institute on Aging : NIA</funding-source>
<award-id>P50 AG005131 || AG</award-id>
</award-group>
</funding-group>
</article-meta>
</front>
</pmc>
<affiliations><list></list>
<tree><noCountry><name sortKey="Clark, Lorraine N" sort="Clark, Lorraine N" uniqKey="Clark L" first="Lorraine N." last="Clark">Lorraine N. Clark</name>
<name sortKey="Crary, John F" sort="Crary, John F" uniqKey="Crary J" first="John F." last="Crary">John F. Crary</name>
<name sortKey="Dewar, Ken" sort="Dewar, Ken" uniqKey="Dewar K" first="Ken" last="Dewar">Ken Dewar</name>
<name sortKey="Haggiagi, Aya" sort="Haggiagi, Aya" uniqKey="Haggiagi A" first="Aya" last="Haggiagi">Aya Haggiagi</name>
<name sortKey="Liu, Xinmin" sort="Liu, Xinmin" uniqKey="Liu X" first="Xinmin" last="Liu">Xinmin Liu</name>
<name sortKey="Nelson, Peter T" sort="Nelson, Peter T" uniqKey="Nelson P" first="Peter T." last="Nelson">Peter T. Nelson</name>
<name sortKey="Santa Maria, Ismael" sort="Santa Maria, Ismael" uniqKey="Santa Maria I" first="Ismael" last="Santa-Maria">Ismael Santa-Maria</name>
<name sortKey="Wasserscheid, Jessica" sort="Wasserscheid, Jessica" uniqKey="Wasserscheid J" first="Jessica" last="Wasserscheid">Jessica Wasserscheid</name>
</noCountry>
</tree>
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</record>
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