Alzheimer Disease Pathology-Associated Polymorphism in a Complex Variable Number of Tandem Repeat Region Within the MUC6 Gene, Near the AP2A2 Gene

• Published in: Journal of neuropathology and experimental neurology Vol. 79; no. 1; pp. 3 - 21
• Main Authors: Katsumata, Yuriko, Fardo, David W, Bachstetter, Adam D, Artiushin, Sergey C, Wang, Wang-Xia, Wei, Angela, Brzezinski, Lena J, Nelson, Bela G, Huang, Qingwei, Abner, Erin L, Anderson, Sonya, Patel, Indumati, Shaw, Benjamin C, Price, Douglas A, Niedowicz, Dana M, Wilcock, Donna W, Jicha, Gregory A, Neltner, Janna H, Van Eldik, Linda J, Estus, Steven, Nelson, Peter T
• Format: Journal Article
• Language: English
• Published: England Oxford University Press 01.01.2020; by American Association of Neuropathologists, Inc
• Subjects: Adaptor Protein Complex 2 - genetics; Adaptor Protein Complex alpha Subunits - genetics; Aged; Aged, 80 and over; Alzheimer Disease - genetics; Alzheimer Disease - pathology; Autopsy; Cohort Studies; Female; Genome-Wide Association Study; Genotype; Humans; Male; Minisatellite Repeats; Mucin-6 - genetics; Neurofibrillary Tangles - genetics; Neurofibrillary Tangles - pathology; Original; Pathology; Polymorphism; Polymorphism, Genetic - genetics; Polymorphism, Single Nucleotide; TDP-43 Proteinopathies - genetics; TDP-43 Proteinopathies - pathology; Digital pathology; ScanScope; AP-2; GWAS; Whole-exome sequencing; ADSP
• ISSN: 0022-3069; 1554-6578; 1554-6578
• DOI: 10.1093/jnen/nlz116

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.