Multi-regional transcriptomic analysis reveals early nociceptive and neuroinflammatory alterations in APP/PS1 mice

BackgroundAlzheimer's disease (AD) is characterized by progressive cognitive decline and neuropsychiatric symptoms, including chronic neuropathic pain. However, the molecular mechanisms linking pain sensitivity to early AD pathology remain poorly understood.

In the present study, 4- to 5-month-old APP/PS1 mice were used to identify molecular signatures of the early pathological stage. Transcriptomic analysis, quantitative real-time RT-PCR (qRT-PCR), immunoblot, and ELISA analyses were performed to assess region-specific gene expression, neuroinflammation, and synaptic protein levels in pain-related regions.

Although memory behaviors remained unchanged in 4-5-month-old APP/PS1 mice, these mice showed an increase in whole-brain Aβ plaque burden. Transcriptomic analysis and qRT-PCR revealed distinct region-specific gene expression changes. Plin4 was downregulated in the DRG, spinal cord, thalamus, and hippocampus of APP/PS1 mice. Rps3a3 and Prnp were significantly upregulated in both the spinal cord and thalamus, whereas Hif3a and Serpina3f were significantly upregulated in the thalamus and hippocampus. These gene alterations were closely involved in inflammatory responses and synaptic plasticity. Immunoblot and ELISA analyses in these pain-related regions demonstrated increased TNF-α and IL-1β levels, as well as reduced expression of synaptic proteins, indicating enhanced neuroinflammation and synaptic loss in the early stages of APP/PS1 mice.

These findings support the presence of neuroinflammation and synaptic dysfunction in pain-processing circuits as early molecular events in APP/PS1 mice, suggesting that nociceptive alterations may represent an early feature of the pathological stage of AD.