An important pathologic feature of AD is the formation of extracellular senile plaques in the brain, whose major components are small peptides called ?-amyloid (A? Multiple lines of evidence suggest that A?s the prime culprit forAD pathogenesis. Therefore, factors mediating the level of A? would potentially be used therapeutically for disease intervention. A? peptides are derived from ? amyloid precursor protein (APP) through sequential cleavages by the ? secretase BACE1 and the ?- secretase complex (consisting of presenilin, nicastrin, APH-1 and PEN2). Since APP and relevant secretases are all transmembrane proteins and traffic through the secretory pathway in a highly regulated fashion, perturbation of their intracellular trafficking may affect dynamic interactions among these proteins, thus altering APP processing/A? generation and contributing to AD pathology. SNX8 belongs to the sorting nexin (SNX) family whose members are proposed to mediate membrane trafficking and protein sorting. SNX8 is localized to early endosomes and has been described to be involved in endosome to TGN trafficking of Shiga toxin and ricin, but the endogenous cargo for SNX8 remains elusive. Recently, the yeast ortholog of SNX8, Mvp1p was identified as a potential enhancer of A? toxicity in a yeast model of A? toxicity. In addition, several single nucleotide polymorphisms of the human SNX8 gene were found to be associated with late onset AD. In our preliminary studies, we also noticed that the level of SNX8 is dramatically decreased in AD brains. In addition, we found that although overexpression of SNX8 does not affect A? induced cell death, it increases A? secretion, whereas downregulation of SNX8 has the opposite effect. Furthermore, overexpression of SNX8 alters subcellular localization of APP and increases its cell surface level. Herein, we hypothesize that SNX8 plays an important role in AD through regulating intracellular trafficking of AD- associated proteins and thus A? generation. In this proposal we will carry out detailed studies to determine whether SNX8 mediates APP processing/A? generation through regulating intracellular trafficking of APP and/or related secretases. We will ascertain the change of SNX8 levels in brain samples of AD patients and AD mice. Furthermore, we will study whether overexpression of SNX8 can ameliorate AD-like disease phenotypes in Tg2576 AD mice by AAV injection. Finally, we will generate brain-specific SNX8 transgenic mice and cross them with Tg2576 mice to further determine the rescuing effect of SNX8 overexpression. Together, our results will elucidate the involvement of SNX8 in AD and the underlying mechanism, identifying a new therapeutic target for disease intervention.

Public Health Relevance

Alzheimer's disease (AD) is one of the most important areas in medical research today and so far there is no cure or meaningfully effective treatment for this devastating neurodegenerative disorder. Demonstration of SNX8 as an important player in AD will have a significant impact on basic research and developing new strategies for treating AD.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Exploratory/Developmental Grants (R21)
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Cell Death and Injury in Neurodegeneration Study Section (CDIN)
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Petanceska, Suzana
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Sanford-Burnham Medical Research Institute
La Jolla
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Feng, Tuancheng; Niu, Mengmeng; Ji, Chengxiang et al. (2016) SNX15 Regulates Cell Surface Recycling of APP and A? Generation. Mol Neurobiol 53:3690-3701
Huang, Timothy Y; Zhao, Yingjun; Li, Xiaoguang et al. (2016) SNX27 and SORLA Interact to Reduce Amyloidogenic Subcellular Distribution and Processing of Amyloid Precursor Protein. J Neurosci 36:7996-8011
Wang, Xin; Huang, Timothy; Zhao, Yingjun et al. (2014) Sorting nexin 27 regulates A? production through modulating ?-secretase activity. Cell Rep 9:1023-33