Researchers identify somatic brain mutations related to Alzheimer's disease

The researchers have identified somatic mutations in the brain that may contribute to the development of Alzheimer's disease. Their conclusions were published in the journal Nature Communications last week.

Decades of research have identified hereditary mutations leading to early familial AD. Hereditary mutations, however, are at the origin of at most half of sporadic cases of late onset AD, in which there is no evidence of anemia. family history of the disease. But the genetic factors responsible for the other half of these sporadic cases have not been clearly defined.

Prof. Jeong Ho Lee, KAIST, badyzed the DNA present in post-mortem hippocampal formations and in blood samples collected from 70-96 year olds with AD and controls of the same age . They specifically searched for non-inherited somatic mutations in their brains using deep full-length exome sequencing.

The team developed a bioinformatics pipeline that allowed them to detect somatic single nucleotide (SNV) changes in the low-level brain – mutations involving substitution of a single nucleotide for another nucleotide. Somatic brain SNVs have been reported and accumulate throughout our lives and can sometimes be badociated with various neurological diseases.

The number of somatic SNVs did not differ between individuals with AD and controls without dementia. Interestingly, somatic SNVs in the brains of those affected appear about 4.8 times slower than in the blood. When the team performed gene enrichment tests, 26.9% of MA brain samples had pathogenic brain SNVs known to be related to hyperphosphorylation of tau proteins, which was found to be in the brain. one of the main features of the MA.

Then, they identified a pathogenic SNV in the PIN1 gene, a cis / trans isomerase that balances phosphorylation in tau proteins, present in the brain of a patient with Alzheimer's disease. They found that the mutation was 4-fold more abundant in AT8-positive – a marker of hyperphosphorylated tau proteins – in the entorhinal cortex than in the global tissue of the hippocampus. In addition, in a series of functional badays, they observed the mutation resulting in a loss of PIN1 function and such haploinsignity deficiency increased phosphorylation and aggregation of tau proteins.

Our study provides new information on molecular genetic factors at the origin of Alzheimer's disease and other neurodegenerative diseases potentially related to somatic mutations in the brain. "

Professor Jeong Ho Lee, KAIST School of Medical Sciences and Engineering

The team plans to extend their study to a larger cohort to establish stronger links between these somatic brain mutations and the pathogenesis of Alzheimer's disease.