Genetic changes differed, increased in people with Alzheimer's disease


Date:
April 20, 2022
Source:
Brigham and Women's Hospital
Summary:
Researchers found that changes accumulated in the brain cells of
patients with Alzheimer's disease at a faster rate, potentially
explaining why brain cells die and revealing new pathways to target
for treatment.



FULL STORY ========================================================================== Inside brain cells, errors in DNA can accumulate as we age. But in
patients with Alzheimer's disease, these errors -- known as somatic
mutations -- may build up at a faster rate. A new study by investigators
from Brigham and Women's Hospital and Boston Children's Hospital found
that patients with Alzheimer's disease (AD) have a greater number of
somatic mutations in their brain cells and that these mutations differed
from people without Alzheimer's disease. The team's results are published
in Nature.


==========================================================================
"As we age, neurons are known to accumulate somatic mutations. In AD
neurons, however, we see more mutations and DNA alterations," said lead
author Michael B. Miller, MD, PhD, of the Department of Pathology at
the Brigham. "Our results suggest that AD neurons experience genomic
damage that causes immense stress on cells and creates dysfunction among
them. These findings may explain why many brain cells die during AD."
The team conducted its study using single-cell whole genome sequencing
of 319 hippocampal and prefrontal cortex neurons of patients with or
without AD to determine the link 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 greater
number of mutations termed somatic single-nucleotide variants (sSNVs)
in patients with AD. Theorizing that the large number of mutations
is the result of increased DNA oxidation, researchers then measured 8-Oxoguanine, an indicator of oxidative stress and DNA damage, and found
that AD neurons were in fact more oxidized.

Ultimately, the discovery of accumulating DNA alterations in AD neurons provides researchers with a window into molecular and cellular events in
AD pathogenesis. "Our findings suggest that the sheer number of oxidative lesions and somatic mutations we observed in AD neurons may contribute
to its pathology," said Miller.

The authors acknowledge two main study limitations. First, two groups
were primarily studied: patients with no neurologic disease and those with advanced AD based on the Braak staging system. In the future, researchers
are eager to study the neurons of individuals with intermediate-stage
AD. Second, while single-cell, whole-genome sequencing was feasible
for the preliminary studies, the authors note that there are advanced
methods that allow for an in-depth analysis of each strand of DNA that
should be explored in the future.

"In the future, we are eager to elucidate how the observed mutations in
AD neurons cause neuronal cell death and are dedicated to aiding in the discovery of novel treatments that target these pathways," Miller said.

Disclosures:Christopher A. Walsh is a paid consultant (cash, no equity)
to Third Rock Ventures and Flagship Pioneering (cash, no equity) and is
on the Clinical Advisory Board (cash and equity) of Maze Therapeutics. No research support is received. These companies did not fund and had no
role in the conception or performance of this research project.

Funding:This work was supported by the National Institutes of Health
(K08 AG065502,T32 HL007627, T32 GM007753, T15 LM007098, R00 AG054748,
K01 AG051791, R01 NS032457-20S1, R01 AG070921, DP2 AG072437), the Brigham
and Women's Hospital Program for Interdisciplinary Neuroscience through
a gift from Lawrence and Tiina Rand, the donors of the Alzheimer's
Disease Research program of the BrightFocus Foundation (A20201292F), the
Doris Duke Charitable Foundation Clinical Scientist Development Award (2021183), Suh Kyungbae Foundation, the F616 Prime Foundation, and the
Allen Discovery Center program, a Paul G. Allen Frontiers Group advised
program of the Paul G. Allen Family Foundation.

Paper cited: Miller MB et al. "Somatic genomic changes in single
Alzheimer's disease neurons" Nature 2022 DOI: 10.1038/s41586-022-04640-1

========================================================================== Story Source: Materials provided by Brigham_and_Women's_Hospital. Note:
Content may be edited for style and length.


========================================================================== Journal Reference:
1. Miller, M.B., Huang, A.Y., Kim, J. et al. Somatic genomic changes in
single Alzheimer's disease neurons. Nature, 2022 DOI:
10.1038/s41586-022- 04640-1 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/04/220420112913.htm

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