SNX15 Regulates Cell Surface Recycling of APP and Aβ Generation

Abstract

Amyloid-β (A(β) peptide plays an essential role in the pathogenesis of Alzheimer's disease (AD) and is generated from amyloid-β precursor protein (APP) through sequential proteolytic cleavages by β-site APP cleaving enzyme 1 (BACE1) and γ-secretase. Trafficking dysregulation of APP, BACE1 and γ-secretase may affect Aβ generation and disease pathogenesis. Sorting nexin 15 (SNX15) is known to regulate protein trafficking. Here we report that SNX15 is abundantly expressed in mouse neurons and astrocytes. In addition, we show that although not affecting the protein levels of APP, BACE1 and γ-secretase components and the activity of BACE1 and γ-secretase, overexpression and downregulation of SNX15 reduces and promotes Aβ production, respectively. Furthermore, we find that overexpression of SNX15 increases APP protein levels in cell surface through accelerating APP recycling, whereas downregulation of SNX15 has an opposite effect. Finally, we show that exogenous expression of human SNX15 in the hippocampal dentate gyrus by adeno-associated virus (AAV) infection can significantly reduce Aβ pathology in the hippocampus and improve short-term working memory in the APPswe/PSEN1dE9 double transgenic AD model mice. Together, our results suggest that SNX15 regulates the recycling of APP to cell surface and thus its processing for Aβ generation.

VPS35 regulates cell surface recycling and signaling of dopamine receptor D1

“…Mouse neuroblastoma N2a cells and Human embryonic kidney 293T (HEK 293T) cells were maintained as previously described (Feng, et al, 2015). Dopaminergic neurons were isolated from the ventral midbrain of wild-type C57BL/6 mice at embryonic days 17-18 (E17-18) and cultured in Neurobasal (Gibco) medium supplemented with B27 (Gibco), GlutaMAX-1, penicillin (100 units/ml), and streptomycin (100 μg/ml), following a published protocol (Lin, et al, 2012).…”

“…These assays were carried out following previously described protocols (Feng, et al, 2015,Wang, et al, 2013). Briefly, cells were labeled with EZ-Link ™ Sulfo-NHS-SS-Biotin (Thermo Scientific) at 4°C for cell surface protein biotinylation.…”

Altered RNA metabolism due to a homozygousRBM7mutation in a patient with spinal motor neuropathy

“…This variant has been reported with very low frequency previously (Supplementary Material, Table S1). Mutations in SNX15 , a novel sorting nexin involved in protein trafficking (21) have not been associated with human disease to date, and recent data suggests that this protein is important for cell surface recycling of APP and Aβ generation (22). Given its function, it is more unlikely to be causative for the SMA-like phenotype, however we cannot exclude completely that it contributes to the clinical manifestation of the disease.…”

Overexpression of SNX3 Decreases Amyloid-β Peptide Production by Reducing Internalization of Amyloid Precursor Protein

“…Here, we focused on SNX3, inspired by the finding that SNPs occur in the SNX3 gene in AD patients [33]. We employed an overexpression approach, which has been used in several previous studies to investigate SNX functions [17, 23, 27]. It can be assumed that overexpression of a protein such as SNX3 alters the function of the pathway in which it normally functions, but overexpression may potentially cause nonspecific effects.…”

“…Subsequently, several studies have linked other SNXs with different aspects of APP processing. For instance, SNX15 regulates the cell surface recycling of APP [17], SNX33 promotes α-secretase cleavage of APP [18], SNX27 influences Aβ generation by controlling the assembly of γ-secretase [19], and SNX6 and SNX12 regulate the transport of BACE1, the main β- secretase [20, 21]. …”