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Nat Commun. 2019 Jul 12;10(1):3090. doi: 10.1038/s41467-019-11000-7.

Brain somatic mutations observed in Alzheimer's disease associated with aging and dysregulation of tau phosphorylation.

Author information

1
Biomedical Science and Engineering Interdisciplinary Program, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, 34141, Republic of Korea.
2
Center for Supercomputing Applications, Division of National Supercomputing, Korea Institute of Science and Technology Information, Daejeon, 34141, Republic of Korea.
3
Department of Biochemistry and Biomedical Sciences, College of Medicine, Seoul National University, Seoul, 03080, Republic of Korea.
4
Neuroscience Research Institute, College of Medicine, Seoul National University, Seoul, 03080, Republic of Korea.
5
Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, 34141, Republic of Korea.
6
Department of Biomedical Systems Informatics, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, 03722, South Korea.
7
Laboratory of Brain Research, Stanley Medical Research Institute (SMRI), 9800 Medical Center Drive, Suite C-050, Rockville, MD, 20850, USA.
8
Center for Cognition and Sociality, Institute for Basic Science (IBS), Daejeon, 34126, Republic of Korea.
9
Center for Supercomputing Applications, Division of National Supercomputing, Korea Institute of Science and Technology Information, Daejeon, 34141, Republic of Korea. codegen@kisti.re.kr.
10
Biomedical Science and Engineering Interdisciplinary Program, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, 34141, Republic of Korea. jhlee4246@kaist.ac.kr.
11
Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, 34141, Republic of Korea. jhlee4246@kaist.ac.kr.

Abstract

The role of brain somatic mutations in Alzheimer's disease (AD) is not well understood. Here, we perform deep whole-exome sequencing (average read depth 584×) in 111 postmortem hippocampal formation and matched blood samples from 52 patients with AD and 11 individuals not affected by AD. The number of somatic single nucleotide variations (SNVs) in AD brain specimens increases significantly with aging, and the rate of mutation accumulation in the brain is 4.8-fold slower than that in AD blood. The putatively pathogenic brain somatic mutations identified in 26.9% (14 of 52) of AD individuals are enriched in PI3K-AKT, MAPK, and AMPK pathway genes known to contribute to hyperphosphorylation of tau. We show that a pathogenic brain somatic mutation in PIN1 leads to a loss-of-function mutation. In vitro mimicking of haploinsufficiency of PIN1 aberrantly increases tau phosphorylation and aggregation. This study provides new insights into the genetic architecture underlying the pathogenesis of AD.

PMID:
31300647
PMCID:
PMC6626023
DOI:
10.1038/s41467-019-11000-7
[Indexed for MEDLINE]
Free PMC Article

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