Unique transcriptomic alterations in 5XFAD;PS19 mouse model identify glial lipid dysregulation and coordinated...

Area of Science:

• Neuroscience
• Genomics
• Pathology

Background:

• Alzheimer's disease (AD) is characterized by amyloid beta (Aβ) plaques and tau tangles.
• The combined effect of Aβ and tau on brain transcriptomic programs is not well understood.

Purpose of the Study:

• To investigate the transcriptomic changes in the brain resulting from combined amyloid beta and tau pathology in mouse models.
• To identify conserved molecular pathways and cellular interactions relevant to human Alzheimer's disease.

Main Methods:

• High-quality, sex-balanced single-nucleus RNA sequencing was performed on 5XFAD (Aβ), PS19 (tau), and combined 5XFAD;PS19 mouse models.
• Transcriptomic data were analyzed to identify distinct and overlapping molecular programs associated with single and combined pathologies.

Main Results:

• Combined Aβ and tau pathology prominently disrupted glial lipid metabolism and immune pathways at the network level.
• Immune and synaptic alterations were coordinated between microglia and oligodendrocytes under combined pathology.
• Pathway-level alterations, particularly in immune, lipid, and cell cycle programs, showed strong concordance with human AD datasets.

Conclusions:

• This study provides a high-quality transcriptomic resource for dissecting multicellular mechanisms in AD.
• The identified pathways highlight potential therapeutic targets for a systems pharmacology approach in Alzheimer's disease.
• The findings underscore the translational relevance of specific pathway alterations observed in mouse models to human AD.