A novel function of CD44 in the pathogenesis of Alzheimer’s disease

Abstract Background Alzheimer’s disease is the main cause of dementia, which is believed to progress with Aβ, neurofibrillary tangle (NFT) and neuroinflammation. CD44 is a transmembrane glycoprotein acts as a receptor for extracellular matrix (ECM). It was firstly found as a receptor for hyaluronic acid (HA). CD44 is cleaved by α‐ or γ‐secretase, becoming soluble form. This fragment activates and modulates several genes related with cell survival. The binding of low molecular weight of HA and CD44, activates NLRP3 inflammasome, and inflammatory cytokines boosts cohesion of HA and CD44. Previous reports indicated that CD44 upregulation was shown in early stage of AD, and amyloid increases CD44 expression. Other researchers illustrated that applying siRNA of CD44 reduced Aβ toxicity, indicating that CD44 participates in Aβ metabolism. Method A total of 38 mice were randomly divided into 4 groups according to their genotype; WT (Control group), CD44 −/− , 5xFAD (AD model), and 5xFAD;CD44 −/− . Behavioural tests were conducted during the age of 8.5 months. We performed Morris Water Maze (MWM) to analyze cognition level. After 7 days of behaviour test, brain tissue was collected by PBS perfusion and analyzed through quantitative real‐time‐PCR(RT‐qPCR), western blot, and immunofluorescence. Result In MWM, 5xFAD;CD44 −/− male mice showed restored cognition level through probe day result. In molecular analysis, Aβ plaque significantly reduced in both cortex and hippocampus of 5xFAD;CD44 −/− mice compared to 5xFAD mice. Inflammatory factors, such as nlrp3, il‐1b, also reduced in the cortex of 5xFAD;CD44 −/− mice. Conclusion Our data indicated that CD44 plays a pivotal role in Aβ plaque formation, leading to cognition impairment. Significant changes in amyloid plaque level were shown, as well as an reduction of inflammatory factors in the brains of 5xFAD;CD44 −/‐ mice. With these results, drugs blocking CD44 would be a strong candidate for the treatment of Alzheimer’s disease. Further studies are needed to clear the mechanism of AD pathology associated with CD44.