Alzheimer Disease Pathology-Associated Polymorphism in a Complex Variable Number of Tandem Repeat Region Within the
Yuriko Katsumata1, David W Fardo1, Adam D Bachstetter1
1Sanders-Brown Center on Aging (YK, DWF, ADB, SCA, W-XW, AW, LJB, BGN, QH, ELA, SA, IP, DAP, DMN, DWW, GAJ, LJVE, PTN); Department of Biostatistics (YK, DWF); Spinal Cord & Brain Injury Research Center (ADB); Department of Neuroscience (ADB, DWW, LJVE); Department of Epidemiology (ELA); Department of Neurology (DWW, GAJ); Department of Physiology (BCS, SE); and Department of Pathology (W-XW, JHN, PTN), University of Kentucky, Lexington, Kentucky.
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.
Insights
Genetic variations in Mucin 6 (MUC6) near Adaptor Related Protein Complex 2 Subunit Alpha 2 (AP2A2) are linked to late-onset Alzheimer disease (LOAD) pTau pathology severity. Longer MUC6 repeat regions correlate with increased neocortical tau pathology.
Area of Science:
- Neuroscience
- Genetics
- Pathology
Background:
- Late-onset Alzheimer disease (LOAD) is a complex neurodegenerative disorder.
- Genetic factors play a significant role in LOAD pathogenesis.
- Phosphorylated tau (pTau) proteinopathy is a hallmark of LOAD.
Purpose of the Study:
- To investigate the association between genetic polymorphisms in Mucin 6 (MUC6) and Adaptor Related Protein Complex 2 Subunit Alpha 2 (AP2A2) and LOAD.
- To determine if MUC6 variable number tandem repeat (VNTR) region size correlates with pTau pathology severity in the neocortex.
- To examine the expression and localization of AP2A2 in LOAD brains.
Main Methods:
- Polymerase Chain Reaction (PCR) analysis of MUC6 VNTR region size in genomic DNA.
- Quantitative digital pathology to assess pTau burden in neocortical brain samples.
- Analysis of AP2A2 gene expression in brain tissue.
- Double-label immunofluorescence to study protein colocalization.
Main Results:
- A significant association was found between MUC6 VNTR region size and neocortical pTau pathology severity in two independent cohorts.
- Longer MUC6 VNTR regions were correlated with increased pTau pathology.
- AP2A2 expression was lower in individuals with longer VNTR regions and frequently colocalized with neurofibrillary tangles in LOAD brains.
Conclusions:
- Polymorphism in a repeat-rich region near AP2A2, specifically within MUC6, is associated with neocortical pTau proteinopathy in LOAD.
- The unique repetitive nature of this polymorphism may explain why it was missed by previous genome-wide association studies.
- AP2A2 protein localization suggests a potential role in LOAD neurofibrillary tangle formation.
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