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Background <p>The hippocampus is selectively vulnerable to Alzheimer’s disease (AD), but the spatially resolved, cell-type-specific drivers of this susceptibility remain unknown, hindering the development of targeted therapies.</p> Methods <p>We employed an integrated causal-spatial approach, combining single-nucleus RNA sequencing (snRNA-seq) from 53 post-mortem AD brains, multi-omics triangulation (Mendelian randomization and Bayesian colocalization), and cross-species spatial mapping in human cohorts and 5xFAD mice to identify drivers of hippocampal vulnerability.</p> Results <p>We identified a novel astrocyte-microglia co-pathology axis centered on <i>EFEMP1</i> and <i>GALNT10</i>. Causal inference prioritized this axis, supported by an <i>EFEMP1</i> plasma protein quantitative trait locus (pQTL) with an exceptional effect size (OR = 7.96) and dual epigenetic-transcriptional regulation of microglial <i>GALNT10</i>. The axis demonstrated hippocampus-specific co-expression in humans (<i>R</i> = 0.81, <i>p</i> &lt; 0.001), pathological amplification in 5xFAD mice (tM1 = 0.77 ± 0.04 vs. WT 0.69 ± 0.04, <i>p</i> &lt; 0.001), and focal enrichment near Aβ plaques (<i>EFEMP1</i>: <i>r</i> = -0.79; <i>GALNT10</i>: <i>r</i> = -0.67, <i>p</i> &lt; 0.001). Mechanistically, it forms a core interactome with <i>EGFR</i> and <i>TIMP3</i>, coupling extracellular matrix (ECM) dysregulation with neuroinflammation.</p> Conclusions <p>Our study defines the <i>EFEMP1</i>-<i>GALNT10</i> axis as a spatially coordinated driver of hippocampal vulnerability in AD. The integrated causal-spatial pipeline provides a generalizable framework for translating genetic associations into spatially resolved therapeutic targets.</p>

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Targeting the astrocyte-microglia EFEMP1-GALNT10 axis: a spatially programmable therapeutic strategy for hippocampal vulnerability in Alzheimer’s disease

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月11日

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  • Junting Liu,
  • Jing Liu,
  • Yujian Fan,
  • Congcong Liu,
  • Jingrong Cao,
  • Haixia Ma,
  • Yuli Hou,
  • Shuo Gao,
  • Peichang Wang

摘要

Background

The hippocampus is selectively vulnerable to Alzheimer’s disease (AD), but the spatially resolved, cell-type-specific drivers of this susceptibility remain unknown, hindering the development of targeted therapies.

Methods

We employed an integrated causal-spatial approach, combining single-nucleus RNA sequencing (snRNA-seq) from 53 post-mortem AD brains, multi-omics triangulation (Mendelian randomization and Bayesian colocalization), and cross-species spatial mapping in human cohorts and 5xFAD mice to identify drivers of hippocampal vulnerability.

Results

We identified a novel astrocyte-microglia co-pathology axis centered on EFEMP1 and GALNT10. Causal inference prioritized this axis, supported by an EFEMP1 plasma protein quantitative trait locus (pQTL) with an exceptional effect size (OR = 7.96) and dual epigenetic-transcriptional regulation of microglial GALNT10. The axis demonstrated hippocampus-specific co-expression in humans (R = 0.81, p < 0.001), pathological amplification in 5xFAD mice (tM1 = 0.77 ± 0.04 vs. WT 0.69 ± 0.04, p < 0.001), and focal enrichment near Aβ plaques (EFEMP1: r = -0.79; GALNT10: r = -0.67, p < 0.001). Mechanistically, it forms a core interactome with EGFR and TIMP3, coupling extracellular matrix (ECM) dysregulation with neuroinflammation.

Conclusions

Our study defines the EFEMP1-GALNT10 axis as a spatially coordinated driver of hippocampal vulnerability in AD. The integrated causal-spatial pipeline provides a generalizable framework for translating genetic associations into spatially resolved therapeutic targets.