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

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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 584x) 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.
Publisher
NATURE PUBLISHING GROUP
Issue Date
2019-07
Language
English
Article Type
Article
Citation

NATURE COMMUNICATIONS, v.10

ISSN
2041-1723
DOI
10.1038/s41467-019-11000-7
URI
http://hdl.handle.net/10203/263878
Appears in Collection
MSE-Journal Papers(저널논문)
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