Abstract
Background
Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, neuronal apoptosis, and amyloid‑β (Aβ) deposition. Dysregulation of the WNT/β‑catenin signaling pathway contributes to AD pathogenesis, yet the upstream regulatory mechanisms, particularly those involving long non‑coding RNAs (lncRNAs), remain unclear. This study investigated the neuroprotective role and molecular mechanism of lncRNA Loc646329 in AD models.Methods and results
Analysis of publicly available human Alzheimer's disease sequencing datasets was performed to examine the expression patterns of Loc646329 and miR-150 in AD and control brain sample. Subcellular localization and interaction with miR‑150 were examined using fluorescence in situ hybridization, AGO2‑RNA immunoprecipitation, and dual‑luciferase reporter assays in SH‑SY5Y cells. Functional assays, including CCK-8, EdU incorporation, Annexin V-FITC/PI flow cytometry, and TUNEL staining, demonstrated that Loc646329 overexpression improved cell viability and reduced apoptosis under Aβ1-42-induced neurotoxic conditions. Mechanistically, Loc646329 localized predominantly in the cytoplasm and directly interacted with miR-150. MiR-150 mimic experiments further indicated that the effects of Loc646329 on GSK3β phosphorylation, β-catenin stabilization, and WNT/β-catenin signaling were at least partly miR-150-dependent. In APP/PS1 mice, stereotaxic injection of AAV‑Loc646329 into the hippocampus improved spatial learning and memory in the Morris water maze, reduced Aβ plaque burden, and increased β‑catenin activation.Conclusions
These findings provide preclinical evidence that the Loc646329/miR-150/WNT signaling axis contributes to neuronal survival and modulates AD-related pathological changes. Loc646329 may therefore represent a candidate molecular regulator for further investigation; however, additional validation in primary or human-derived neuronal models and clinical samples is required before its therapeutic relevance can be established.