Alzheimer disease pathology-associated polymorphism in a complex variable number of tandem repeat region within the MUC6 gene, near the AP2A2 gene

Yuriko Katsumata, David W. Fardo, Adam D. Bachstetter, Sergey C. Artiushin, Wang Xia Wang, Angela Wei, Lena J. Brzezinski, Bela G. Nelson, Qingwei Huang, Erin L. Abner, Sonya Anderson, Indumati Patel, Benjamin C. Shaw, Douglas A. Price, Dana M. Niedowicz, Donna W. Wilcock, Gregory A. Jicha, Janna H. Neltner, Linda J. Van Eldik, Steven EstusPeter T. Nelson

Research output: Contribution to journalArticlepeer-review

15 Scopus citations

Abstract

We found evidence of late-onset Alzheimer disease (LOAD)-associated genetic polymorphism within an exon of Mucin 6 (MUC6) and immediately downstream from another gene: Adaptor Related Protein Complex 2 Subunit Alpha 2 (AP2A2). PCR analyses on genomic DNA samples confirmed that the size of the MUC6 variable number tandem repeat (VNTR) region was highly polymorphic. In a cohort of autopsied subjects with quantitative digital pathology data (n=119), the size of the polymorphic region was associated with the severity of pTau pathology in neocortex. In a separate replication cohort of autopsied subjects (n=173), more pTau pathology was again observed in subjects with longer VNTR regions (p=0.031). Unlike MUC6, AP2A2 is highly expressed in human brain. AP2A2 expression was lower in a subset analysis of brain samples from persons with longer versus shorter VNTR regions (p=0.014 normalizing with AP2B1 expression). Double-label immunofluorescence studies showed that AP2A2 protein often colocalized with neurofibrillary tangles in LOAD but was not colocalized with pTau proteinopathy in progressive supranuclear palsy, or with TDP-43 proteinopathy. In summary, polymorphism in a repeat-rich region near AP2A2 was associated with neocortical pTau proteinopathy (because of the unique repeats, prior genome-wide association studies were probably unable to detect this association), and AP2A2 was often colocalized with neurofibrillary tangles in LOAD.

Original languageEnglish
Pages (from-to)3-21
Number of pages19
JournalJournal of Neuropathology and Experimental Neurology
Volume79
Issue number1
DOIs
StatePublished - Jan 1 2020

Bibliographical note

Publisher Copyright:
© 2019 American Association of Neuropathologists, Inc.

Keywords

  • ADSP
  • AP-2
  • Digital pathology
  • GWAS
  • ScanScope
  • Whole-exome sequencing

ASJC Scopus subject areas

  • General Medicine

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