Single Nucleus Transcriptome Data from Alzheimer's Disease Mouse Models Yield New Insight into Pathophysiology

Area of Science:

• Neuroscience
• Genomics
• Molecular Biology

Background:

• Utilizes 5XFAD and Trem2 knockout (T2KO) mouse models, which are crucial for studying Alzheimer's disease (AD) pathology.
• Focuses on the hippocampus, a brain region vital for memory and heavily impacted by AD.

Purpose of the Study:

• To investigate alterations in hippocampal gene expression and polyadenylation site usage in 5XFAD and T2KO mouse models of AD.
• To identify specific molecular changes associated with genetic mutations relevant to Alzheimer's disease.

Main Methods:

• Employs single-nucleus RNA sequencing (snRNA-seq) on hippocampal cells from 5XFAD and T2KO mice.
• Utilizes Seurat for differential gene expression (DEG) analysis and Sierra for differential transcript usage (DTU) analysis.
• Performs Ingenuity Pathway Analysis (IPA) to explore biological pathways affected by the identified genetic changes.

Main Results:

• Identified numerous differentially expressed genes (DEGs) in both neuronal and glial cells in 5XFAD and T2KO models compared to wild type.
• Detected shared differential transcript usage (DTU) patterns in neuronal and glial subtypes between the two AD mouse models.
• IPA revealed significant enrichment of 'FXR/RXR Activation', 'LXR/RXR Activation', and 'Acute Phase Response Signaling' pathways across multiple cell types.

Conclusions:

• Findings underscore the role of energy imbalance and inflammation in hippocampal cell types during AD pathogenesis.
• Highlights the utility of 5XFAD and T2KO mouse models for dissecting AD-related molecular mechanisms.
• Suggests that DEG and DTU analyses in specific cell types can reveal key pathways in AD development.