Basic Science and Pathogenesis

Area of Science:

• Neuroscience
• Genetics
• Aging Research

Background:

• Age is a primary risk factor for Alzheimer's disease (AD), with individual susceptibility influenced by brain aging heterogeneity.
• Understanding genetic contributions to aging variability is key to differentiating normal aging from early AD pathology.

Purpose of the Study:

• To identify normal brain aging signatures across nine wild-type mouse strains.
• To capture biological variability in aging trajectories often missed in single-strain studies.
• To investigate the influence of genetic background on brain aging and its relation to AD.

Main Methods:

• RNA-sequencing of brain hemispheres from nine wild-type mouse strains at three age timepoints (4, 12, 24 months).
• Identification of strain-specific aging signatures by comparing gene expression at later timepoints to the baseline (4 months).
• Differential expression analysis, gene set enrichment, and Weighted Gene Co-expression Network Analysis (WGCNA) to identify aging-associated pathways and common signatures.

Main Results:

• Limited and variable strain-specific aging signatures at 12 months, with distinct signatures emerging by 24 months.
• Common disruptions in immune response and inflammation observed across strains by 24 months, with varying magnitude and rate.
• Strain-specific overlaps with AD-related processes identified, including synaptic downregulation (NOD), proteostasis disruptions (WSB, NZO, 129), and altered lipid metabolism (CAST).

Conclusions:

• Brain aging involves both shared and strain-specific molecular mechanisms, with genetic background playing a critical role in neurodegeneration risk.
• Aging signatures intensify over time, with significant pathway enrichment at 24 months indicating accelerated aging processes.
• Studying heterogeneous aging trajectories is essential for understanding dynamic age-related changes and the impact of baseline genetic differences.