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Trafficking Regulation of Proteins in Alzheimer's Disease

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Trafficking Regulation of Proteins in Alzheimer's Disease Jiang et al. Molecular Neurodegeneration 2014, 9:6 http://www.molecularneurodegeneration.com/content/9/1/6 REVIEW Open Access Trafficking regulation of proteins in Alzheimer’s disease Shangtong Jiang1,2†, Yanfang Li2†, Xian Zhang2, Guojun Bu2,3, Huaxi Xu1,2,4 and Yun-wu Zhang2* Abstract The β-amyloid (Aβ) peptide has been postulated to be a key determinant in the pathogenesis of Alzheimer’s disease (AD). Aβ is produced through sequential cleavage of the β-amyloid precursor protein (APP) by β- and γ-secretases. APP and relevant secretases are 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 Aβ generation and accelerating disease pathogenesis. Herein, we review recent progress elucidating the regulation of intracellular trafficking of these essential protein components in AD. Keywords: α-secretase, Amyloid beta (A4) precursor protein, β-secretase, Beta-site APP-cleaving enzyme 1, γ-secretase, A Disintegrin and Metalloprotease 10, Alzheimer’s disease, Trafficking Introduction APP β-carboxyl-terminal fragment (β-CTF) is then Alzheimer’s disease (AD) is a progressive neurodegenera- cleaved by the γ-secretase complex within the lipid bilayer, tive disorder characterized clinically by cognitive and resulting in the production of Aβ peptide and the APP memory dysfunction, accompanied by classical hallmark intracellular domain (AICD). Alternatively, processing pathologies such as intraneuronal neurofibrillary tangles within the non-amyloidogenic pathway involves APP (NFTs) and extracellular amyloid plaques [1-3]. NFTs cleavage by α-secretase within the Aβ domain. The α- are enriched with hyperphosphorylated microtubule-asso- cleavage releases the extracellular domain of APP called ciated protein tau (MAPT) [2], which can be phospho- sAPPα. The remaining membrane-bound fragment is rylated by multiple protein kinases. Amyloid plaques called APP α-CTF and can be further processed by γ- comprise a heterogeneous population of proteolytically- secretase to generate AICD and a p3 peptide that is rap- generated small β-amyloid peptides (Aβ) [1,4,5]. Mounting idly degraded [1,10]. Whether APP is processed through evidence indicates that overproduction/aggregation of Aβ the amyloidogenic pathway by β-secretase or through the in the brain is a primary cause of AD. According to the non-amyloidogenic pathway by α-secretase greatly de- “amyloid cascade hypothesis”,neurotoxicAβ may trigger pends on colocalization between APP and these secre- a cascade of complex neurodegenerative events leading to tases, which in turn is dependent on their subcellular co- synaptic dysfunction, NFT formation and eventually distribution. Hence, comprehensive elucidation of the neuron loss in affected brain areas [6-9]. mechanisms responsible for regulating the intracellular Aβ is generated from amyloid beta (A4) precursor pro- trafficking of APP and related secretases are important as- tein (APP). APP can be processed by amyloidogenic and pects in our understanding of AD and AD pathogenesis. non-amyloidogenic pathways. Amyloidogenic processing involves initial APP cleavage by β-secretase within the ectodomain, leading to the release of a soluble APP frag- Regulated trafficking of APP ment called sAPPβ. The remaining membrane-anchored APP and its trafficking route within the cell APP is a ubiquitously-expressed type I transmembrane protein belonging to a family comprising three members: * Correspondence: [email protected] APP, APP-like protein 1 and APP-like protein 2, all of †Equal contributors 2Institute of Neuroscience, College of Medicine, Xiamen University, Xiamen, which share a highly conserved extracellular region con- Fujian 361102, China taining Kunitz protease inhibitor (KPI), E1 and E2 do- Full list of author information is available at the end of the article mains [11,12]. However, only APP contains the Aβ region. © 2014 Jiang et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Jiang et al. Molecular Neurodegeneration 2014, 9:6 Page 2 of 13 http://www.molecularneurodegeneration.com/content/9/1/6 There are three major APP protein isoforms: APP770, APP structure and post-translational modification affect its APP751 and APP695. The longer isoforms APP770 and trafficking APP751 contain the KPI domain, whereas APP695 is The intracellular domain of APP is key in regulating APP devoid of this domain and is the predominant iso- trafficking through interactions with various cytosolic traf- form expressed in the brain [13,14]. APP participates in ficking factors. A highly conserved YENPTY motif (amino multiple cellular events including cell adhesion, neurite acids 682–687 in APP695) within APP intracellular do- outgrowth, neuronal migration, protein transport, cell sig- main is the major binding site for a number of intracel- naling and synaptogenesis. For a more complete review lular adaptors such as APP-binding, family A (APBA, on the function of APP please see [1]. previously called MINT) members and APP-binding, Full-length APP is synthesized in the endoplasmic family B, member 1 (APBB1, previously called Fe65) [23]. reticulum (ER) and transported through the Golgi/trans- Mutation within this motif can attenuate the interna- Golgi network (TGN) apparatus where APP undergoes lization of APP, thereby decreasing Aβ generation [24]. posttranslational modifications such as glycosylation and Recently, the extracellular domain of APP has also been phosphorylation during maturation. TGN is also the shown to affect its trafficking: the KPI domain located in major site of resident APP in neurons [15-17]. Full-length the APP751 extracellular region promotes sorting of APP can be transported to the cell surface in TGN- APP751 to the plasma membrane, accompanied by de- derived secretory vesicles. At the plasma membrane APP creased Aβ formation in comparison to the neuronal is either cleaved by α-secretase to produce sAPPα [18] or enriched, KPI domain-absent APP695 isoform. Mutation re-internalized within clathrin-coated vesicles to the endo- in the KPI domain of APP751 results in its retention in some. APP in the endosome can either be recycled back the ER and elevated Aβ production [25]. to cell surface or be delivered to the lysosome for degra- APP can be phosphorylated at sites S655 and T668 (based dation (Figure 1) [19,20]. Aβ production involves multiple on APP695 numbering) and APP phosphorylation may also intracellular organelles [15-17,21,22]. Typically, increased affect its trafficking. A YTSI (amino acids 653–656 in APP delivery to or decreased APP internalization from the APP695) motif within the APP intracellular domain is cell surface favors the non-amyloidogenic processing, associated with APP internalization and Golgi polarized whereas elevated retention of APP in acidic compartments sorting in MDCK epithelial cells; and phosphorylation of such as endosomes promotes amyloidogenic processing S655 within this motif promotes APP retrieval from the and consequent Aβ production. endosome to TGN [26,27]. Phosphorylation of APP T668 Figure 1 Typical trafficking route of APP, BACE1, α-secretase and γ-secretase. Newly synthesized APP, BACE1, α-secretase and γ-secretase traffic through the secretory pathway, from the ER to Golgi/TGN and to the plasma membrane, during which process retrieval may occur and APP may be cleaved to generate Aβ. At the plasma membrane APP is largely subjected to non-amyloidogenic processing by α-secretase to release sAPPα. Un-cleaved APP and various secretases at the plasma membrane may undergo endocytosis via early endosome to late endosome/lysosome for degradation. Acidic endosome/lysosome provides optimal environment for BACE1 activity and APP is mainly subjected to amyloidogenic processing for Aβ production in these compartments. In addition, a fraction of these proteins in endosome can be either recycled back to plasma membrane or retrieved back to TGN. Jiang et al. Molecular Neurodegeneration 2014, 9:6 Page 3 of 13 http://www.molecularneurodegeneration.com/content/9/1/6 facilitates amyloidogenic APP processing and Aβ ge- (intracellularly or extracellularly) and specific linker neration [28]. Although direct evidence linking T668 proteins involved. A new member of LDLR family, phosphorylation and APP trafficking is scarce, T668 phos- LRP10, is found to shuttle between plasma membrane, phorylation may interfere APP’s interaction with other pro- TGN and endosome [45,46], and interacts with the APP teins and thus potentially affect its processing/trafficking ectodomain to sequester APP in Golgi compartments, [29]. Indeed, phosphorylated APP is found to be preferen- thereby reducing APP β-processing and consequent Aβ tially enriched at nerve terminals and plasma membrane generation [47]. in neurons, and accumulates in pathological damaged The best characterized LDLR family member in AD is regions of AD brains [30]. SORL1, a multifunctional neuronal receptor that binds APP can be ubiquitinated for its proteasomal degra- APOE and APP. Genetic studies
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