Loss of WDR23 slows the rate of age-related cognitive decline with elevated amyloid burden

BackgroundWDR23 is a regulator of cellular proteostasis and oxidative stress response processes that are critically involved in the pathogenesis of Alzheimer's disease (AD). Dysregulation of these pathways can contribute to amyloid-β (Aβ) and tau pathologies, ultimately leading to cognitive impairment.ObjectiveWe explored the effects of <i>Wdr23</i> knockout on key AD-related pathologies, including transcriptomic changes, Aβ and tau pathology, and cognitive function in the 3xTg-AD mouse model of early onset familial AD.MethodsTranscriptomic analysis of hippocampal tissue was performed to identify <i>Wdr23</i>-dependent gene expression changes across age groups. Aβ and tau pathology was assessed via immunohistochemistry. Behavioral assays were conducted to determine cognitive function and locomotor activity.ResultsTranscriptomic data revealed an age-dependent effect of <i>Wdr23</i> knockout on gene expression, with enrichment of pathways related to cognition and synaptic plasticity, especially middle-age and aged mice. Interestingly, while <i>Wdr23</i> knockout exacerbated amyloid plaque accumulation in older mice, it did not impact tau pathology. Behaviorally, <i>Wdr23</i> knockout mice exhibited improved cognitive function and enhanced activity levels compared to wild-type counterparts, suggesting a dissociation between Aβ pathology and cognitive performance. Additionally, we observed age-related changes in NRF2 target gene activation but declined in <i>Wdr23</i> knockout mice over time.ConclusionsOur findings highlight a complex relationship between proteostasis, amyloid pathology, and cognitive outcomes in AD, warranting further investigation into the specific mechanisms by which <i>Wdr23</i> modulates these processes. This study suggests that targeting proteostasis pathways could offer potential therapeutic benefits, particularly in preserving cognitive function, even in the presence of amyloid pathology.