The Role Of SNX8 In Alzheimer's Disease

One of the neuropathologic hallmarks of Alzheimer's disease(AD)is the presence of senile plaques which consist of ?-amyloid peptide(A?)in the brain.Accumulation of the neurotoxic A? in the brain is central to the pathogenesis of AD.A? is derived from ?-amyloid precursor protein(APP)through sequential cleavages by the ?-secretase and the y-secretase.In addition to amyloidogenic processing,APP can also be cleaved by ?-secretase to form a soluble or secreted APP ectodomain(sAPP-?)that has been shown to be mostly neuro-protective.Some studies suggest that ?-secretase is a membranebound endoprotease which cleaves APP primarily at the plasma membrane,and that ?-secretase and y-secretase are mainly localized in acidic subcellular compartments such as the endosomes and trans-Golgi network(TGN)where ?-secretase cleaves APP.Thus,the subcellular localization and trafficking of APP greatly affects the production of A?.Sorting nexin 8(SNX8)belongs to the sorting nexin protein family,whose members are involved in endocytosis and endosomal sorting and signaling.The function of SNX8 has so far been unknown.In this study,we find that SNX8 colocalizes with early endosome antigen(EEA),suggesting an endosomal localization.Overexpression of SNX8 reduces the level of A? and increases the level of APP and sAPP?,without affecting the y-secretase activity.Downregulation of SNX8 has the opposite effects.Futher studies showed that SNX8 interacts with APP and increases cell surface levels of APP.In addition,we found that SNX8 increases the level of APP without affecting its mRNA level,suggesting that SNX8 regulates APP level posttranscriptionally.Meanwhile,we found that SNX8 protein level was decreased in the brain of AD patients as compared to that of controls.Thus,together our results suggest that SNX8 regulates APP trafficking for its processing,and a possible involvement of SNX8 in AD pathology.Further studies will be needed to elucidate detailed molecular pathways that may render new therapeutics for AD.