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<p>Selective neuronal vulnerability is a hallmark of Alzheimer’s disease (AD), yet the molecular basis of resilience remains poorly understood. Using single-nucleus and spatial transcriptomics to compare neocortical regions affected early (prefrontal cortex, precuneus) or late (primary visual cortex) in AD, we identified a resilient excitatory population in layer 4 of the primary visual cortex expressing <i>RORB</i>, <i>CUX2</i>, and <i>EYA4</i>. Layer 4 neurons in association neocortex shared molecular signatures of resilience. Early-stage resilient neurons upregulated genes associated with synapse maintenance, synaptic plasticity, calcium homeostasis, and neuroprotection (<i>GRIN2A, RORA, NRXN1, NLGN1, NCAM2, FGF14, NRG3, NEGR1</i>, <i>CSMD1)</i>. We identified <i>KCNIP4</i>, which encodes a voltage-gated potassium channel-interacting protein, as a key resilience factor consistently upregulated during early stages of AD pathology. AAV-mediated overexpression of <i>Kcnip4</i> in male <i>App</i><sup>SAA</sup> mice reduced the expression of activity-dependent genes <i>Arc</i> and <i>c-Fos</i>, suggesting compensatory mechanisms against neuronal hyperexcitability. Our dataset provides a resource for investigating mechanisms underlying resilience to neurodegeneration.</p>

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Molecular signatures of resilience to Alzheimer’s disease in neocortical layer 4 neurons

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月31日

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  • S. Akila Parvathy Dharshini,
  • Jorge Sanz-Ros,
  • Jie Pan,
  • Weijing Tang,
  • Kristen Vallejo,
  • Yu Chen Liu,
  • Marcos Otero-Garcia,
  • Inma Cobos

摘要

Selective neuronal vulnerability is a hallmark of Alzheimer’s disease (AD), yet the molecular basis of resilience remains poorly understood. Using single-nucleus and spatial transcriptomics to compare neocortical regions affected early (prefrontal cortex, precuneus) or late (primary visual cortex) in AD, we identified a resilient excitatory population in layer 4 of the primary visual cortex expressing RORB, CUX2, and EYA4. Layer 4 neurons in association neocortex shared molecular signatures of resilience. Early-stage resilient neurons upregulated genes associated with synapse maintenance, synaptic plasticity, calcium homeostasis, and neuroprotection (GRIN2A, RORA, NRXN1, NLGN1, NCAM2, FGF14, NRG3, NEGR1, CSMD1). We identified KCNIP4, which encodes a voltage-gated potassium channel-interacting protein, as a key resilience factor consistently upregulated during early stages of AD pathology. AAV-mediated overexpression of Kcnip4 in male AppSAA mice reduced the expression of activity-dependent genes Arc and c-Fos, suggesting compensatory mechanisms against neuronal hyperexcitability. Our dataset provides a resource for investigating mechanisms underlying resilience to neurodegeneration.