Mechanistic and functional study of lncRNA SNHG3/miR-128-3p/UBR5 axis in neuroinflammation in Alzheimer's disease

Neuroinflammation assumes a pivotal role in Alzheimer's disease (AD) pathogenesis. Long noncoding RNAs (lncRNAs) regulate neuroinflammation through a competitive endogenous RNA (ceRNA) mechanism. This study aimed to explore the mechanism of the SNHG3/miR-128-3p/UBR5 axis in AD-associated neuroinflammation. SNHG3, miR-128-3p, and UBR5 levels were recognized by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). An in vitro AD model was established by Aβ1-42 stimulation in human microglial cells HMC3 and neuronal cells SK‑N‑SH. Cell apoptosis was detected by flow cytometry. Enzyme-linked immunosorbent assay (ELISA) and oxidative stress indicators were used to evaluate the neuroinflammatory phenotype. Morris water maze (MWM) test assesses the spatial learning and memory abilities of amyloid precursor protein/presenilin 1 (APP/PS1) mice with AAV-si-SNHG3. Serum SNHG3 was clearly upregulated in AD patients and negatively related to MMSE score (r = -0.691, P < .001). SNHG3 had diagnostic potential for AD (AUC = 0.847, 95% CI = 0.806-0.888, sensitivity = 75.63%, specificity = 76.88%). SNHG3 regulates UBR5 expression by sponges miR-128-3p. Silencing of SNHG3 inhibited M1 polarization (reducing TNF-α, IL-6, and iNOS), promoted M2 polarization (increasing Arg1, IL-10, and TGF-β), inhibited IL-1β release, suppressed neuronal apoptosis, and mitigated oxidative stress damage (reducing MDA and increasing SOD) via the miR-128-3p/UBR5 axis in Aβ-stimulated HMC3 cells. SNHG3 also contributes to Aβ‑induced neuronal apoptosis, inflammation, and oxidative stress in SK‑N‑SH cells. AAV-si-SNHG3 significantly enhances spatial learning and memory abilities of APP/PS1 mice, and inhibits neuroinflammation and oxidative stress in the hippocampus. This study is the first to elucidate that SNHG3 could regulate microglial polarization and neuroinflammation through the SNHG3/miR-128-3p/UBR5 axis.