期刊
JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY
卷 79, 期 1, 页码 3-21出版社
OXFORD UNIV PRESS INC
DOI: 10.1093/jnen/nlz116
关键词
ADSP; AP-2; Digital pathology; GWAS; ScanScope; Whole-exome sequencing
资金
- Common Fund of the Office of the Director of the NIH
- NCI
- NHGRI
- NHLBI
- NIDA
- NIMH
- NINDS [R01 NS017950]
- ADSP
- NIA [U01 AG032984, R01 AG033193, R01AG023629, R01AG15928, R01AG20098, R01s AG054076, AG049607, AG033040, U24AG021886, U01AG016976, U24AG041689]
- National Heart, Lung, and Blood Institute (NHLBI)
- NHLBI [HL105756, RC2HL102419, HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN26820 1100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, HHSN268201100012C, R01-HL70825, HHSN268201200036C, HHSN268200800007C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, U01HL080295, U01HL130114, N01-HC-25195, HHSN268201500001I]
- National Institute on Aging (NIA) R01 grant [AG033193]
- Austrian Science Fond (FWF) [P20545-P05, P13180]
- Medical University of Graz
- Austrian Science Fund (FWF) [I904]
- EU Joint Programme-Neurodegenerative Disease Research (JPND)
- Steierm_arkische Krankenanstalten Gesellschaft
- Austrian Research Promotion agency (FFG) [827462]
- Austrian National Bank (Anniversary Fund) [15435]
- NIH (NHLBI) [U01 2U01HL096812, 2U01HL096814, 2U01HL096899, 2U01HL096902, 2U01HL096917]
- NIH (NINDS) [U01 2U01HL096812, 2U01HL096814, 2U01HL096899, 2U01HL096902, 2U01HL096917]
- NIH (NIA) [U01 2U01HL096812, 2U01HL096814, 2U01HL096899, 2U01HL096902, 2U01HL096917]
- NIH (NIDCD) [U01 2U01HL096812, 2U01HL096814, 2U01HL096899, 2U01HL096902, 2U01HL096917]
- National Institute of Neurological Disorders and Stroke (NINDS)
- European Commission FP6 STRP [018947 (LSHG-CT-2006-01947)]
- European Community's Seventh Framework Programme (FP7/2007-2013)/grant by the European Commission under the programme Quality of Life and Management of the Living Resources of 5th Framework Programme [HEALTH-F4-2007201413, QLG2-CT-2002-01254]
- Netherlands Organization for Scientific Research [NWO-RFBR 047.017.043]
- Russian Foundation for Basic Research [NWO-RFBR 047.017.043]
- Erasmus Medical Center, Rotterdam
- Erasmus University, Rotterdam
- Netherlands Organization for Health Research and Development (ZonMw)
- Research Institute for Diseases in the Elderly (RIDE)
- Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports
- European Commission (DG XII)
- municipality of Rotterdam
- Netherlands Organization of Scientific Research NWO Investments [175.010.2005.011, 911-03-012]
- Genetic Laboratory of the Department of Internal Medicine, Erasmus MC
- Research Institute for Diseases in the Elderly [014-93-015]
- Netherlands Genomics Initiative (NGI)/Netherlands Organization for Scientific Research (NWO) Netherlands Consortium for Healthy Aging (NCHA) [050-060-810]
- Human Genome Sequencing Center at the Baylor College of Medicine [U54 HG003273]
- Broad Institute Genome Center [U54HG003067]
- American Genome Center at the Uniformed Services University of the Health Sciences [U01AG057659]
- Washington University Genome Institute [U54HG003079]
- NIH
- Intramural Research Program of the National Institutes of health, National Library of Medicine
- [UF1AG047133]
- [U01AG049505]
- [U01AG049506]
- [U01AG049507]
- [U01AG049508]
- [U01AG052411]
- [U01AG052410]
- [U01 AG052409]
- [U54AG052427]
- Austrian Science Fund (FWF) [P13180] Funding Source: Austrian Science Fund (FWF)
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.
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