Basic Science and Pathogenesis.

Area of Science:

• Neuroscience
• Genomics
• Molecular Biology

Background:

• Alzheimer's disease (AD) is characterized by selective neuronal vulnerability, particularly in RORB-positive excitatory neurons in the entorhinal cortex (EC).
• Understanding the molecular basis of this selective vulnerability is critical for developing targeted AD therapies.
• Not all RORB-positive neurons exhibit vulnerability, suggesting intrinsic molecular differences between subtypes.

Purpose of the Study:

• To identify molecular pathways distinguishing vulnerable from resilient RORB-positive excitatory neuron subtypes in the early stages of AD.
• To leverage single-nucleus RNA sequencing (snRNA-seq) data to uncover transcriptomic signatures associated with neuronal vulnerability in AD.

Main Methods:

• Analysis of snRNA-seq data from postmortem EC tissue of healthy controls and AD patients.
• Utilized Monocle3 trajectory analysis to map cell state progression across Braak stages.
• Performed differential gene expression (DEG) analysis comparing resilient (Q1) and vulnerable (Q4) RORB neuron transcriptomes.

Main Results:

• Identified two distinct RORB-positive neuronal populations in the EC.
• Discovered 537 differentially expressed genes between resilient and vulnerable RORB neurons.
• Vulnerable neurons showed upregulated pathways in supramolecular fiber organization and downregulated pathways in protein translation and quality control.

Conclusions:

• Transcriptomic signatures highlight pathways involved in cytoskeletal organization and proteostasis as key factors in RORB neuron vulnerability in early AD.
• These molecular differences may underlie tau accumulation and neuronal loss in AD.
• Further investigation into these RORB subpopulations could refine understanding of selective neuronal vulnerability mechanisms in AD.