NEW YORK – Somatic mutations that arise in the brain can contribute to the development of Alzheimer's disease, according to a new study.
Somatic mutations accumulate with age in various tissues, but researchers from the Korea Advanced Institute of Science and Technology noted that the role of somatic mutations in the brain in Alzheimer's disease development has been unclear.
By deep sequencing the exomes of post-mortem brain and matched blood samples from 52 individuals who had Alzheimer's disease (AD) and 11 who did not, KAIST's Jeong Ho Lee and his colleagues found that though somatic mutations arise more slowly in the brain, the individuals with Alzheimer's disease had more somatic mutations enriched in tau-related pathways. Hyperphosphorylated tau proteins make up the neurofibrillary tangles that, along with β-amyloid plaques, are characteristic of the disease.
"Brain somatic mutations accumulating with increasing age can modulate the initial appearance of tau pathology in the [hippocampal formation] of AD brains," Lee and his colleagues wrote in their paper, which appeared in Nature Communications today.
Using laser capture microdissection, the researchers isolated and enriched hippocampal neuronal cells from frozen brain tissue blocks from 52 individuals with AD and 11 unaffected individuals. They performed deep exome sequencing of these tissues and matched blood samples, hoping that deep sequencing — they reported an average read depth of 565X for brain samples and 599X for blood samples — would enable them to detect low-level somatic SNVs.
Using the somatic mutation caller MuTect, the researchers uncovered 760 putative SNVs in the brain and 2,846 putative SNVs in blood samples.
Overall, the number of somatic SNVs did not differ between individuals with Alzheimer's disease and unaffected individuals. But brain tissue tended to have fewer somatic SNVs than did blood.
In both tissues, the researchers found somatic SNVs, as expected, accumulate in an age-dependent manner. However, they estimated that somatic SNVs arise at a 4.8-fold faster rate in the blood. Further, they calculated that, each year, 22 somatic SNVs and 106 somatic SNVs arise in hippocampal and blood tissues, respectively.
But of the 268 nonsynonymous somatic SNVs the researchers identified in the brain samples, 65.3 percent were rare and predicted to be putatively pathogenic. These putatively pathogenic somatic SNVs were enriched for involvement in the PI3K-AKT, mitogen-activated protein kinase (MAPK) and AMP-activated protein kinase (AMPK) pathways, the researchers found. All these pathways can modulate tau kinase or phosphatase activity, suggesting that these somatic mutations could be linked to the dysregulation of tau in AD.
One gene the researchers zeroed in on that could affect the phosphorylation of tau protein is PIN1, a peptidyl-prolyl cis-trans isomerase. In mice, loss of its expression is tied to age-dependent hyperphosphorylation of tau and neurofibrillary tangles.
Within their cohort, though, one patient harbored an SNV in PIN1 that affected the catalytic domain. While the SNV was present in all the examined sub-regions of the hippocampus, the researchers noted that its variant allelic frequency varied: in bulk hippocampal tissue it was 1.8 percent, but rose by 4.9 fold to 8.75 percent in neurons in the entorhinal cortex that were AT8-positive — a marker of tau phosphorylation. The mutation was not present, though, in AT8-negative neurons there, suggesting entorhinal cortical neurons with the pathogenic somatic mutation could be the site of origin for tau pathology.
Additionally, in a series of functional assays, the research found that this PIN1 alteration leads to a loss of function and that haploinsufficiency of PIN1 increases tau phosphorylation and aggregation.
"[O]ur study provides new insights into the molecular genetic etiology of AD and other sporadic neurodegenerative disorders potentially linked to somatic mutations in the brain," Lee and his colleagues added in their paper.