Dysregulation of various APP trafficking components in the endosome has been previously implicated in Alzheimer’s disease (AD). Although single nucleotide polymorphisms within the gene locus encoding the endosomal component, SNX8 have been previously associated with AD, how SNX8 levels are altered and its contribution to AD onset is currently unknown. Here, we observe decreased expression of SNX8 in human AD and AD mouse brain. SNX8 predominantly localized to early and late endosomes, where SNX8 overexpression enhanced total APP levels, cell surface APP distribution and consequent soluble APPα cleavage. SNX8 depletion resulted in elevated β-amyloid (Aβ) levels, while SNX8 overexpression reduced Aβ levels in cells and in an APP/PS1 AD mouse model. Importantly, SNX8 overexpression rescued cognitive impairment in APP/PS1 mice. Together, these results implicate a neuroprotective role for SNX8 in enhancing non-amyloidogenic APP trafficking and processing pathways. Given that endosomal dysfunction is an early event in AD, restoration of dysfunctional endosomal components such as SNX8 may be beneficial in future therapeutic strategies.
Oxidative stress is a common feature of neurodegenerative diseases and plays an important role in disease progression. Appoptosin is a pro-apoptotic protein that contributes to the pathogenesis of neurodegenerative diseases such as Alzheimer's disease and progressive supranuclear palsy. However, whether appoptosin mediates oxidative stress-induced neurotoxicity has yet to be determined. Here, we observe that appoptosin protein levels are induced by hydrogen peroxide (H2O2) exposure through the inhibition of proteasomal appoptosin degradation. Furthermore, we demonstrate that overexpression of appoptosin induces apoptosis through the JNK-FoxO1 pathway. Importantly, knockdown of appoptosin can ameliorate H2O2-induced JNK activation and apoptosis in primary neurons. Thus, we propose that appoptosin functions as an upstream regulator of the JNK-FoxO1 pathway, contributing to cell death in response to oxidative stress during neurodegeneration.
Circulating tumor cells (CTCs) are in limited numbers and heterogeneous, making their detection, isolation, and enumeration a major challenge. To overcome these difficulties, we developed a novel method to detect and enumerate CTCs with invasive property. Our assay consists of three simple steps: enrichment, Matrigel invasion assay, and immunostaining. We have validated this method using mouse xenograft tumor models and confirmed its utility in human cancer patients. Our method does not require special equipment and antigen expression for CTC selection, is less likely to be affected by the heterogeneity of the CTCs, and could be applicable to virtually all cancers. Most important, our method enumerates invasive CTCs, which may allow more accurate correlations with clinical outcome and treatment response compared with other CTC detection methods.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.