Search

Ectodomain shedding of the amyloid precursor protein (APP) by the two proteases α- and β-secretase is a key regulatory event in the generation of the Alzheimer disease amyloid β peptide (Aβ). β-Secretase catalyzes the first step in Aβ generation, whereas α-secretase cleaves within the Aβ domain, prevents Aβ generation, and generates a secreted form of APP with neuroprotective properties. At present, little is known about the cellular mechanisms that control APP α-secretase cleavage and Aβ generation. To explore the contributory pathways, we carried out an expression cloning screen. We identified a novel member of the sorting nexin (SNX) family of endosomal trafficking proteins, called SNX33, as a new activator of APP α-secretase cleavage. SNX33 is a homolog of SNX9 and was found to be a ubiquitously expressed phosphoprotein. Exogenous expression of SNX33 in cultured cells increased APP α-secretase cleavage 4-fold but surprisingly had little effect on β-secretase cleavage. This effect was similar to the expression of the dominant negative dynamin-1 mutant K44A. SNX33 bound the endocytic GTPase dynamin and reduced the rate of APP endocytosis in a dynamin-dependent manner. This led to an increase of APP at the plasma membrane, where α-secretase cleavage mostly occurs. In summary, our study identifies SNX33 as a new endocytic protein, which modulates APP endocytosis and APP α-secretase cleavage, and demonstrates that the rate of APP endocytosis is a major control factor for APP α-secretase cleavage. [ABSTRACT FROM AUTHOR]

Sjögren's Syndrome (SS) is an autoimmune pathology of varying prevalence. Its involvement in exocrine glands requires that greater attention be paid to patients' oral health. A cross-sectional study was designed to assess the oral health of subjects with SS in constant medical follow-ups. Variables such as the presence of periodontal infections, decay and alterations in the oral mucosa were analyzed, and the individual's salivary flow was measured. The data were analyzed descriptively and with the chi-squared test, considering p<0.05 as statistically significant. 35 subjects of both sexes were studied, aged between 25 and 82 years, with an age average of 53.9 years; they presented on average 7.9 years after the initial diagnosis. The subjects reported a dental check-up every 6 months in only 9% of cases, whereas the rest had one every 1 or 2 years. All the subjects recounted presenting with dry mouth and associated significantly the ingestion of fluids and teeth brushing to improve the sensation of dryness. The salivary flow was objectively seen to be compromised, showing a significant reduction in those with more time since diagnosis of the disease; more than 90% of subjects exhibited periodontal inflammation and a high level of caries. The mucosa presented a low level of pathology. In conclusion, education in oral health is imperative for subjects with this pathology and more frequent check-ups may be useful in decreasing the levels of oral pathology.

Ectodomain shedding of the amyloid precursor protein (APP) by the two proteases alpha- and beta-secretase is a key regulatory event in the generation of the Alzheimer disease amyloid beta peptide (Abeta). beta-Secretase catalyzes the first step in Abeta generation, whereas alpha-secretase cleaves within the Abeta domain, prevents Abeta generation, and generates a secreted form of APP with neuroprotective properties. At present, little is known about the cellular mechanisms that control APP alpha-secretase cleavage and Abeta generation. To explore the contributory pathways, we carried out an expression cloning screen. We identified a novel member of the sorting nexin (SNX) family of endosomal trafficking proteins, called SNX33, as a new activator of APP alpha-secretase cleavage. SNX33 is a homolog of SNX9 and was found to be a ubiquitously expressed phosphoprotein. Exogenous expression of SNX33 in cultured cells increased APP alpha-secretase cleavage 4-fold but surprisingly had little effect on beta-secretase cleavage. This effect was similar to the expression of the dominant negative dynamin-1 mutant K44A. SNX33 bound the endocytic GTPase dynamin and reduced the rate of APP endocytosis in a dynamin-dependent manner. This led to an increase of APP at the plasma membrane, where alpha-secretase cleavage mostly occurs. In summary, our study identifies SNX33 as a new endocytic protein, which modulates APP endocytosis and APP alpha-secretase cleavage, and demonstrates that the rate of APP endocytosis is a major control factor for APP alpha-secretase cleavage.