# Altered Microglia-Neuron Crosstalk and Regional Heterogeneity in Alzheimer’s Disease Revealed by Single-Nucleus RNA Sequencing

## TL;DR

This study uses single-nucleus RNA sequencing to reveal how microglia and neurons interact differently in various brain regions during Alzheimer’s disease.

## Contribution

The study systematically characterizes region-specific microglia-neuron interactions and identifies THY1 as a potential therapeutic target.

## Key findings

- Four microglial subtypes were identified, with a pseudotime trajectory leading to the DAM phenotype.
- Brain regions show unique microglia-neuron communication patterns, such as the THY1-ITGAX/ITGB2 axis in the PFC and OL.
- THY1 dysregulation correlates with AD pathology across multiple brain regions.

## Abstract

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by irreversible cognitive decline and synaptic dysfunction and represents the most prevalent etiology of dementia, accounting for an estimated 60–70% of all clinically diagnosed cases worldwide. The growing focus on microglia–neuron interactions in AD research highlights their diverse, region-specific responses, which are driven by the functional and pathological heterogeneity across different brain regions. Therefore, investigating the interactions between microglia and neurons is of crucial importance. To explore the regional heterogeneity of microglia–neuron crosstalk in AD, we integrated human single-nucleus RNA sequencing data from the prefrontal cortex (PFC), hippocampus (HPC), and occipital lobe (OL) provided by the ssREAD database. Our study delineated four microglial subtypes and uncovered a pseudotime trajectory activation trajectory leading to the disease-associated microglia (DAM) phenotype. The transition along this trajectory is driven and stabilized by a key molecular switch: the coordinated downregulation of inhibitory factors (e.g., LINGO1) and upregulation of immune-effector and antigen-presentation programs, which collectively establish the pro-inflammatory DAM state. Furthermore, we observed that each brain region displayed unique microglia–neuron communication patterns in response to AD pathology. The PFC and OL engage a THY1-ITGAX/ITGB2 signaling axis; the HPC predominantly utilizes the PTPRM pathway. Notably, THY1 dysregulation strongly correlates with pathology in the PFC, HPC, and OL, suggesting that microglia–neuron crosstalk in AD possesses both heterogeneity and commonality. The main contribution of this study is the systematic characterization of region-specific microglia-neuron interactions and the identification of THY1 as a potential mediator that may be targeted therapeutically to modulate microglial function in affected brain regions.