Sorting nexin-4 regulates ß-amyloid production by modulating ß-site-activating cleavage enzyme-1.

BACKGROUND: Amyloid precursor protein (APP) is cleaved by ß-site amyloid precursor protein-cleaving enzyme 1 (BACE1) to produce ß-amyloid (Aß), a critical pathogenic peptide in Alzheimer's disease (AD). Aß generation can be affected by the intracellular trafficking of APP or its related secretases, which is thus important to understanding its pathological alterations. Although sorting nexin (SNX) family proteins regulate this trafficking, the relevance and role of sorting nexin-4 (SNX4) regarding AD has not been studied yet. METHODS: In this study, human brain tissue and APP/PS1 mouse brain tissue were used to check the disease relevance of SNX4. To investigate the role of SNX4 in AD pathogenesis, several experiments were done, such as coimmunoprecipitation, Western blotting, immunohistochemistry, and gradient fractionation. RESULTS: We found that SNX4 protein levels changed in the brains of patients with AD and of AD model mice. Overexpression of SNX4 significantly increased the levels of BACE1 and Aß. Downregulation of SNX4 had the opposite effect. SNX4 interacts with BACE1 and prevents BACE1 trafficking to the lysosomal degradation system, resulting in an increased half-life of BACE1 and increased production of Aß. CONCLUSIONS: We show that SNX4 regulates BACE1 trafficking. Our findings suggest novel therapeutic implications of modulating SNX4 to regulate BACE1-mediated ß-processing of APP and subsequent Aß generation.

ß-Amyloid is transmitted via neuronal connections along axonal membranes.

OBJECTIVE: ß-amyloid plaque is a critical pathological feature of Alzheimer disease. Pathologic studies suggest that neurodegeneration may occur in a retrograde fashion from axon terminals near ß-amyloid plaques, and that plaque may spread through brain regions. However, there is no direct experimental evidence to show transmission of ß-amyloid. METHODS: Microscopic imaging data of ß-amyloid transmission was acquired in cortical neuron cultures from Sprague-Dawley rat embryos using polydimethylsiloxane (PDMS) microfluidic culture chambers and in brain sections from in vivo ß-amyloid injection. RESULTS: We present direct imaging evidence in cultured cortical neurons, using PDMS microfluidic culture chambers, that ß-amyloid is readily absorbed by axonal processes and retrogradely transported to neuronal cell bodies. Transmission of ß-amyloid via neuronal connections was also confirmed in mouse brain. ß-Amyloid absorbed by distal axons accumulates in axonal swellings, mitochondria, and lysosomes of the cell bodies. Interestingly, dynasore, an inhibitor of dynamin, which is a protein indispensable for endocytosis, did not prevent retrograde transport of ß-amyloid, indicating that ß-amyloid is absorbed onto axonal membranes and transmitted via them to the cell body. Dynasore did decrease the transneuronal transmission of ß-amyloid, suggesting that this requires the internalization and secretion of ß-amyloid. INTERPRETATION: Our findings provide direct in vitro and in vivo evidence for spreading of ß-amyloid through neuronal connections, and suggest possible therapeutic approaches to blocking this spread.