Changes in neuronal DNA content variation in the human brain during aging.

Area of Science:

• Neuroscience
• Genetics
• Cell Biology

Background:

• The human brain exhibits genetic mosaicism, with some neurons possessing DNA content exceeding the diploid level, originating from chromosome segregation errors.
• While many such neurons are eliminated during development, abnormal copy number variants persist in the mature brain.
• Genomic alterations in neurons may cause instability, affect neuronal viability, and contribute to age-related neurological disorders.

Purpose of the Study:

• To quantify the frequency of neurons with DNA content above the diploid level in the human cerebral cortex.
• To analyze age-related changes in the prevalence of these neurons from the fourth to the ninth decade of life.

Main Methods:

• Utilized slide-based cytometry optimized for DNA quantification of individual neurons.
• Analyzed DNA content in approximately 500,000 neurons per brain from normal human brain samples.
• Compared neuronal DNA content across different age groups.

Main Results:

• An average of 11.5% of cortical neurons displayed DNA content exceeding the diploid level.
• The frequency of neurons with this genomic alteration was highest in younger individuals and decreased with advancing age.
• This suggests a potential decline in the viability of neurons with abnormal DNA content in the aging brain.

Conclusions:

• Genomic variation, specifically DNA content above the diploid level in neurons, may impact neuronal viability in the aging brain.
• This phenomenon could contribute to increased susceptibility to age-related central nervous system (CNS) disorders.
• Consideration of selection bias in "healthy aging brains" is warranted, as DNA content variation may correlate with conditions like Alzheimer's disease.