In Alzheimer’s disease, DNA errors stress cells and cause dysfunction – Harvard Gazette

Inside brain cells, DNA errors can accumulate with age. However, in patients with Alzheimer’s disease, these errors (known as somatic mutations) can accumulate at a faster rate.

New research by researchers from Brigham and Women’s Hospital Boston Children’s Hospital found that patients with Alzheimer’s disease have many somatic mutations in their brain cells, and these mutations are different from those without Alzheimer’s disease.Team results are published in Nature..

“As we grow older, neurons are known to accumulate somatic mutations, but AD neurons show more mutations and DNA changes,” said the lead author. .. Michael B. Miller of Department of Pathology In Brigham. “Our results suggest that AD neurons experience genomic damage that causes enormous stress on cells and causes dysfunction between them. These findings suggest that many brain cells during AD. May explain why he dies. “

The team conducted a study using a single-cell whole-genome sequence of 319 hippocampal and prefrontal neurons in patients with and without AD to determine the association between the number and type of somatic mutations and AD. To better understand the genomic changes that occur in AD neurons, researchers sequenced tissue DNA and discovered a number of mutations called somatic single nucleotide polymorphisms (sSNVs) in AD patients. Theorizing that numerous mutations are the result of increased DNA oxidation, researchers measured 8-oxoguanine, an indicator of oxidative stress and DNA damage, and found that AD neurons were actually more oxidized. Did.

Ultimately, the discovery of DNA changes that accumulate in AD neurons provides researchers with a window to molecular and cellular events in the etiology of AD. “Our findings suggest that the vast number of oxidative lesions and somatic mutations observed in AD neurons may contribute to the pathology,” Miller said. increase.

The author acknowledges the limitations of two major studies. Initially, two groups were primarily studied: patients without neurological disorders and patients with advanced AD based on the Brack staging system. In the future, researchers are keen to study the neurons of individuals with mid-term AD. Second, while preliminary studies allowed single-cell whole-genome sequencing, the authors state that there are advanced methods that allow detailed analysis of each strand of DNA that needs to be investigated in the future. increase.

“In the future, we want to elucidate how the mutations observed in AD neurons cause neuronal cell death, and we are dedicated to helping to find new therapies that target these pathways. “Mr. Miller said.

Disclosure: Christopher A. Walsh is a paid consultant (cash, no equity) for Third Rock Ventures and Flagship Pioneering (cash, no equity) and a member of the Maze Therapeutics Clinical Advisory Board (cash and equity). increase. We do not receive research support. These companies did not fund and were not involved in the conception or implementation of this research project.

This work is from the National Institutes of Health (K08 AG065502, T32 HL007627, T32 GM007753, T15 LM007098, R00 AG054748, K01 AG051791, R01 NS032457-20S1, R01 AG070921, DP2 AG072437), Brigam and Women’s Hospital for Interdisciplinary Neuroscience. Supported by the program from Bright Focus Foundation (A20201292F), Doris Duke Charitable Foundation Clinical Scientist Development Award (2021183), Suh Kyungbae Foundation, F616 Prime Foundation, and Lawrence and Tiina Rand, donors of Allen’s Alzheimer’s disease research program. Through Gifts Discovery Center Program, Paul G. Allen Frontier Group-Paul G. Allen Family Foundation Advisory Program.