This study presents a comprehensive single-nucleus transcriptomic atlas of the basal forebrain across developmental and early ageing stages in mice. It identifies distinct molecular regulatory patterns in basal forebrain cell subclasses and highlights pathways related to cholesterol metabolism, DNA repair, and neurodegeneration, particularly in cholinergic neurons linked to Alzheimer’s disease.
Background
The basal forebrain is a critical brain region involved in learning, memory, and attention, with neurons that undergo structural and functional changes during ageing. Age-related impairments in this region include calcium homeostasis imbalance, receptor loss, and synaptic degeneration, contributing to vulnerability in neurodegenerative diseases such as Alzheimer’s disease. Understanding molecular changes in basal forebrain neurons during development and ageing is essential for elucidating mechanisms underlying cognitive decline and neurodegeneration. Single-nucleus RNA sequencing enables detailed characterization of cellular heterogeneity and transcriptional dynamics in this region.
Data Highlights
Age (months/days)
Mouse Strain
Sample Size (n)
4 days
C57BL/6N
8
14 days
C57BL/6N
8
3 months
C57BL/6N
6
9 months
C57BL/6N
6
15 months
C57BL/6N
6
9 months
5xFAD (Alzheimer’s model)
6
15 months
5xFAD (Alzheimer’s model)
6
Key Findings
Distinct molecular regulatory patterns and ageing-related pathways were identified in basal forebrain cell subclasses across development and early ageing.
Cholinergic neuron subtype CN-2 showed increased activity of regulons linked to Srebf2 and Zmiz1, which regulate cholesterol/lipid metabolism, DNA damage repair, and death receptor signaling.
CN-2 subtype is the primary contributor to alterations in the NRXN signaling pathway, implicated in synaptic function and neurodegeneration.
Integrative analysis with 5xFAD Alzheimer’s disease mouse model revealed four potential regulatory networks involved in neurodegenerative processes.
Single-nucleus RNA sequencing provided a high-resolution temporal gene expression atlas from postnatal day 4 to 15 months, capturing developmental and ageing transitions.
Clinical Implications
The identification of specific molecular pathways and regulatory networks in basal forebrain cholinergic neurons provides potential targets for therapeutic intervention in ageing-related cognitive decline and Alzheimer’s disease. Understanding cholesterol metabolism dysregulation and DNA repair mechanisms in these neurons may guide development of strategies to preserve basal forebrain function. This atlas serves as a valuable resource for designing cell type-specific treatments aimed at mitigating neurodegeneration.
Conclusion
This comprehensive transcriptomic atlas elucidates the molecular underpinnings of basal forebrain development and early ageing, highlighting key pathways implicated in neurodegeneration. It offers a foundational resource to advance research and therapeutic approaches targeting basal forebrain subclasses in ageing and Alzheimer’s disease.
References
Original Article 2024 -- Comprehensive Single-Nucleus Transcriptomic Atlas of the Basal Forebrain Uncovers Varied Age-Related Pathways
