ArticlebioRxiv : the preprint server for biology2025
Transcriptomic and protein analysis of human cortex reveals genes and pathways linked to NPTX2 disruption in Alzheimer's disease.
Article in bioRxiv : the preprint server for biology, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
The expression of NPTX2, a neuronal immediate early gene (IEG) essential for excitatory-inhibitory balance, is altered in the earliest stages of cognitive decline that anticipate Alzheimer's disease (AD). Here, we use NPTX2 as a point of reference for Omics studies to identify genes and pathways linked to its position in AD onset and progression. We integrated bulk RNA sequencing from 575 middle temporal gyrus (MTG) samples across four cohorts together with targeted proteomics in the same samples using parallel reaction monitoring-mass spectrometry in 135 representative cases, focusing on 20 curated proteins spanning synaptic, trafficking, lysosomal, and regulatory categories. NPTX2 RNA and protein were significantly reduced in AD, and to a lesser extent in mild cognitive impairment (MCI) samples. BDNF, VGF, SST, and SCG2 correlated with both NPTX2 mRNA and protein. We identified NPTX2 correlated synaptic and mitochondrial programs that were negatively correlated with lysosomal and chromatin/stress modules. Gene set enrichment analysis (GSEA) of NPTX2 correlations across all samples confirmed broad alignment with synaptic and mitochondrial compartments, while more NPTX2-specific associations were observed with proteostasis and translation regulator pathways, which were weakened in AD. In contrast, correlation of NPTX2 protein with transcriptomic profiles revealed negative associations with stress-linked transcription regulator RNAs (FOXJ1, ZHX3, SMAD5, JDP2, ZIC4), which were strengthened in AD. Studies position NPTX2 as a hub of an activity-regulated "plasticity cluster" (BDNF, VGF, SST, SCG2) that encompasses interneuron function and is embedded on a neuronal/mitochondrial integrity axis that is inversely coupled to lysosomal/chromatin-stress programs. In AD, these transcript-level correlations broadly weaken, and stress-linked transcriptional regulators become more prominent, suggesting a role in NPTX2 loss of function.
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Registered trials
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