Researchers at UTHealth Houston conducted a study investigating gene expression and regulation at single-cell levels. The study identified disruptions in gene function within three brain regions of patients diagnosed with sporadic early onset Alzheimer's disease.
The findings were published in the journal Science Advances.
Early onset Alzheimer's disease affects approximately 5% to 10% of Alzheimer's patients under 65. Among these, 10% have mutations in APP, PSEN1, and PSEN2 genes. The remaining 90% are classified as sporadic early onset Alzheimer's, a rare and aggressive form that manifests before age 65. The genetic basis for this form of the disease is largely unknown, highlighting it as an understudied area.
Zhongming Zhao, PhD, MS, professor and Chair for Precision Health at McWilliams School of Biomedical Informatics at UTHealth Houston, stated that previous research often focused on cells in a single brain region from late-onset Alzheimer's patients. This study utilized a new single-cell technology to map genes across three brain regions in sporadic early onset Alzheimer's, providing a detailed view of molecular signals and gene regulations.
Researchers employed advanced single-nucleus multiomics techniques to study brains affected by early onset Alzheimer's disease. This method isolates cell nuclei, enabling the study of biological information layers to understand gene regulation and expression in specific cell types.
The study analyzed three brain regions involved in Alzheimer's progression: the prefrontal cortex, entorhinal cortex, and hippocampus. This contrasts with prior research that primarily focused on only the prefrontal cortex. Over 76,000 cell nuclei from these regions were analyzed.
Andi Liu, PhD, a graduate research assistant at UTHealth Houston, noted that a goal of the study was to compare consistent and unique signals across the three brain regions at a single-cell level, which had not been previously done in this disease context.
Key Findings
The study identified the most severe gene disruptions within the entorhinal cortex and hippocampus, aligning with their symptomatic involvement in sporadic early onset Alzheimer's disease.
Researchers found malfunctions in specific gene regulators, or 'switches.' Two key regulators identified were RFX4 in astrocytes (support cells) and IKZF1 in microglia (brain immune cells).
These regulators control genes influencing brain cell communication and the brain's immune system response. Cell pathways involved in neuroinflammation and neuronal communication junctions were altered in the presence of Alzheimer's pathogens.
The research also examined glial cells and astrocytes, noting astrocytes' role in inflammation and potential for unintended damage to brain cells when responding to amyloid plaques.
Implications
While some findings align with late-onset Alzheimer's disease progression, sporadic early onset Alzheimer's exhibited unique patterns, including shared vulnerabilities with conditions such as schizophrenia and bipolar disorder.
The study suggests potential therapeutic targets aimed at restoring normal gene regulation and intercellular communication, which could lead to precision medicine approaches in Alzheimer's research.
Paul Schulz, MD, professor of neurology at McGovern Medical School at UTHealth Houston, stated that the study provides insights into how brain cells, glia, and microglia interact in Alzheimer's disease, which can inform future research and the development of rationally designed treatments.
Research Team
The research team included additional authors from UTHealth Houston's School of Public Health, Center for Precision Health at McWilliams School of Biomedical Informatics, and McGovern Medical School's Department of Neurology. An author from Baylor College of Medicine also contributed.