Dual platform spatial transcriptomics reveals parvalbumin interneuron subtype vulnerability in mouse models of...

Area of Science:

• Neuroscience
• Genomics
• Molecular Biology

Background:

• Alzheimer's disease (AD) is a neurodegenerative disorder causing cognitive decline.
• The retrosplenial cortex (RSC) and its parvalbumin-expressing (PV+) interneurons are early sites of AD pathology.
• Understanding molecular changes in these vulnerable neurons is crucial.

Purpose of the Study:

• To investigate molecular alterations in PV+ interneurons within the RSC in a mouse model of AD.
• To identify distinct transcriptional subpopulations and disease-associated molecular markers.
• To demonstrate the utility of integrated spatial transcriptomics platforms.

Main Methods:

• Utilized a dual-platform spatial transcriptomics approach: GeoMx Digital Spatial Profiler (DSP) and Xenium In Situ.
• Analyzed transcriptomic profiles of PV+ and NeuN+ neurons in the RSC of female 5xFAD mice.
• Employed non-negative matrix factorization and k-means clustering to identify disease-associated metagenes.

Main Results:

• Identified distinct transcriptional subpopulations within RSC PV+ interneurons.
• Found significant down-regulation of Dner, Gad1, and Pvalb in transgenic (TG) mice, indicating impaired GABAergic signaling.
• Confirmed findings through cross-validation with RNAscope and immunohistochemistry, ensuring robustness.

Conclusions:

• PV+ interneurons exhibit heterogeneity and molecular vulnerabilities in Alzheimer's disease.
• The study highlights specific molecular markers associated with AD pathology in these neurons.
• Integrated spatial transcriptomics is a powerful tool for discovering disease-associated neuronal subtypes.