Interneuron transcriptomics reveals pathologic markers of Alzheimer's disease progression

Area of Science:

• Neuroscience
• Molecular Biology
• Genomics

Background:

• Alzheimer's disease (AD) is characterized by an imbalance in neuronal excitation and inhibition, potentially due to interneuron dysfunction.
• Understanding the specific molecular changes in different neuronal subtypes during AD progression is crucial for identifying therapeutic targets.

Purpose of the Study:

• To spatially profile the transcriptome of neuronal subtypes in a mouse model of Alzheimer's disease (5XFAD) compared to controls.
• To identify early and late-stage molecular alterations in excitatory and inhibitory neurons relevant to AD pathophysiology.

Main Methods:

• Single-cell spatial transcriptomic profiling of neuronal subtypes in 5XFAD and control mice at early and late disease stages.
• Differential gene expression analysis and pathway enrichment analysis to compare neuronal subtypes and disease stages.

Main Results:

• Early-stage interneurons showed alterations in RNA/protein processing and neurodegenerative pathways, while excitatory neurons showed changes in axon guidance and synapse pathways.
• Late-stage excitatory neurons displayed classical neurodegenerative pathways, which were absent in early-stage excitatory neurons.
• Late-stage interneurons exhibited neuronal, synapse, cellular, cancer, and infection pathways, suggesting complex roles beyond canonical AD pathways.

Conclusions:

• Neurodegenerative pathways appear to be involved earlier in interneurons than in excitatory neurons in Alzheimer's disease.
• These findings suggest a potential earlier role for inhibitory neuron dysfunction in AD pathogenesis.
• Transcriptomic insights provide a foundation for developing targeted therapies for Alzheimer's disease.