Open AccessAlzheimer Disease Pathology-Associated Polymorphism in a Complex Variable Number of Tandem Repeat Region Within the MUC6 Gene, Near the AP2A2 Gene
Author(s) -
Yuriko Katsumata,
David W. Fardo,
Adam D. Bachstetter,
Sergey Artiushin,
WangXia Wang,
Angela Wei,
Lena J Brzezinski,
Bela G Nelson,
Qinghong Huang,
Erin L. Abner,
Sonya Anderson,
Indumati Patel,
Benjamin Shaw,
Douglas A. Price,
Dana M. Niedowicz,
Donna W Wilcock,
Gregory A. Jicha,
Janna H. Neltner,
Linda J. Van Eldik,
Steven Estus,
Peter T. Nelson
Publication year - 2019
Publication title -
journal of neuropathology and experimental neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.441
H-Index - 164
eISSN - 1554-6578
pISSN - 0022-3069
DOI - 10.1093/jnen/nlz116
Subject(s) - biology , pathology , gene , tandem repeat , exon , variable number tandem repeat , progressive supranuclear palsy , genetics , allele , medicine , genome , atrophy
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.