A National Institutes of Health (NIH)-funded study has identified significant age-related changes in the immune environment of the hippocampus, the brain region responsible for learning and memory. The findings suggest that immune remodeling may begin during midlife and could help explain how aging contributes to the persistent brain inflammation associated with Alzheimer’s disease and other neurodegenerative disorders.
“Aging is the single largest risk factor for dementia, but our understanding of how it drives disease is still incomplete,” said Richard Hodes, M.D., director of the NIH’s National Institute on Aging (NIA). “This previously hidden microglial shift, uncovered through advances in technology and scientific thinking, may provide an important clue to help complete the puzzle.”
Brain Immune Cells Begin Changing During Midlife
Researchers from the University of California, San Diego, the New York Genome Center and the University of California, Irvine, used advanced single-cell analysis techniques to examine postmortem hippocampal tissue from 40 neurologically healthy adults between 20 and 95 years of age.
The analysis showed that microglia—the brain’s primary immune cells—gradually decrease between approximately ages 50 and 75. During the same period, they appear to be replaced by cells with stronger inflammatory signals and characteristics more closely associated with immune cells originating in the peripheral bloodstream.
The discovery challenges the long-held belief that microglia, which develop during embryonic growth, remain in the brain and continuously renew themselves throughout a person’s lifetime.
Advanced Genomic Tools Reveal the Origins of Brain Immune Cells
To investigate how aging affects the human brain at the cellular level, the research team combined conventional gene-expression analysis with newer technologies that map the genome’s three-dimensional structure and chemical modifications, collectively known as the epigenome.
“Gene expression tells us what a cell is doing today, but epigenetic signatures preserve information about where a cell came from,” said first author Nathan Zemke, Ph.D., director of single-cell genomics at the UC San Diego Center for Epigenomics. “By combining these approaches, we uncovered a major shift in the identity and lineage of immune cells in the aging human brain that gene-expression data alone would not have revealed.”
Using these combined methods, the researchers identified changes in immune cell identity and origin that would likely have remained undetected through gene-expression analysis alone.
Aging May Also Weaken the Blood-Brain Barrier
The study found additional evidence of age-related decline in cells that help maintain the blood-brain barrier—the protective boundary that regulates which substances can move from the bloodstream into the brain.
Aging was also linked to widespread, coordinated changes in the physical organization of the genome across multiple types of brain cells.
“The progressive structural disruptions were closely linked to shifts in gene regulation and cell identity, potentially revealing a fundamental feature of aging in the human brain,” said Bing Ren, Ph.D., a corresponding author of the study, scientific director and CEO of the New York Genome Center, and professor of genetics and development at Columbia University.
Potential Connections to Alzheimer’s Disease and Neurodegeneration
Future studies will investigate why resident microglia decline with age and whether the newly identified transition in immune cell populations directly contributes to Alzheimer’s disease and other age-related neurological conditions.
“Understanding these cellular transitions may provide new opportunities to develop interventions that preserve brain function and reduce vulnerability to neurodegenerative disease,” said Xiangmin Xu, Ph.D., professor and director of the Center for Neural Circuit Mapping at UC Irvine and a corresponding author of the study.
NIH supported the research through NIA grants R01AG067153 and R01AG082127, as well as the NIH Common Fund 4D Nucleome (4DN) program grant 1U01DA052769. The work is part of a collection of studies supported by the 4DN program and published in Science and Science Advances. Together, the studies offer new insight into how the genome’s three-dimensional organization influences human development, aging and disease.
Source: www.sciencedaily.com