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01-11-2012 | Original Paper

The MAPT H1 haplotype is associated with tangle-predominant dementia

Authors: Ismael Santa-Maria, Aya Haggiagi, Xinmin Liu, Jessica Wasserscheid, Peter T. Nelson, Ken Dewar, Lorraine N. Clark, John F. Crary

Published in: Acta Neuropathologica | Issue 5/2012

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 (MAPT). Haplotype analysis demonstrates a strong association between TPD and the MAPT 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 MAPT followed by association analysis shows an association between TPD and two polymorphisms in the MAPT 3′ untranslated region (UTR). These results support the hypothesis that haplotype-specific variation in the MAPT 3′ UTR underlies an Aβ-independent mechanism for neurodegeneration in TPD.

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Title: The MAPT H1 haplotype is associated with tangle-predominant dementia
Authors: Ismael Santa-Maria
Aya Haggiagi
Xinmin Liu
Jessica Wasserscheid
Peter T. Nelson
Ken Dewar
Lorraine N. Clark
John F. Crary
Publication date: 01-11-2012
Publisher: Springer-Verlag
Published in: Acta Neuropathologica / Issue 5/2012
Print ISSN: 0001-6322
Electronic ISSN: 1432-0533
DOI: https://doi.org/10.1007/s00401-012-1017-1

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The MAPT H1 haplotype is associated with tangle-predominant dementia

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