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The Use of Pharmacological Retromer Chaperones in Alzheimer's

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The Use of Pharmacological Retromer Chaperones in Alzheimer's Neurotherapeutics (2015) 12:12–18 DOI 10.1007/s13311-014-0321-y REVIEW The Use of Pharmacological Retromer Chaperones in Alzheimer’s Disease and other Endosomal-related Disorders Diego E. Berman & Dagmar Ringe & Greg A. Petsko & Scott A. Small Published online: 4 December 2014 # The American Society for Experimental NeuroTherapeutics, Inc. 2014 Abstract The retromer is an evolutionary conserved Endosomes, Retromer, and Alzheimer’sDisease multiprotein complex involved in the sorting and retrograde trafficking of cargo from endosomal compartments to the A common emerging theme in the research field of age-related Golgi network and to the cell surface. The neuronal retromer neurodegenerative diseases is that of endosomal dysfunction traffics the amyloid precursor protein away from the [1]. Specifically in Alzheimer’s disease (AD), primary evi- endosomes, a site where amyloid precursor protein is enzy- dence pinpointing the endosome as the intracellular site of matically cleaved into pathogenic fragments in Alzheimer’s dysfunction was described in a seminal series of histological disease. In recent years, deficiencies in retromer-mediated studies performed by Cataldo et al. [2]. They showed that transport have been implicated in several neurological and endosomes in the entorhinal cortex and the cornu ammonis non-neurological diseases, including Parkinson’sdisease,sug- subfields of the hippocampal formation are abnormally en- gesting that improving the efficacy of the retromer trafficking larged during the earliest stages of disease. Remarkably, the pathway would result in decreased pathology. We recently distribution of abnormally enlarged endosomes was nearly identified a new family of small molecules that appear to diagnostic of the disease, with very little overlap in the size stabilize the interaction between members of the retromer of endosomes observed in age-matched controls. Additional- complex and enhance its function in neurons: the retromer ly, they showed that carrying the apolipoprotein E4 gene pharmacological chaperones. Here we discuss the role of these variant, the strongest genetic risk factor for late-onset AD, molecules in the improvement of retromer trafficking and further enhanced endosomal enlargement, and that abnormal endosomal dysfunction, as well as their potential as therapeu- enlargement did not occur as part of normal aging. The near tics for neurological and non-neurological disorders. uniformity of the abnormality in patients with late-onset “spo- radic” AD suggests a convergence of pathogenic mechanisms leading to endosomal enlargement. In the case of AD, this is Key Words Retromer . Alzheimer’s disease . particularly important as the endosomal compartment of the neurodegeneration . pharmacological chaperones cell is one of the main sites where amyloid precursor protein β : (APP) interacts with -site APP-cleaving enzyme 1 D. E. Berman (*) S. A. Small (BACE1), initiating a pathogenic process leading to the accu- ’ The Taub Institute for Research on Alzheimer s Disease and the mulation of a number of putatively neurotoxic proteolytic Aging Brain, and Department of Pathology and Cell Biology, β Columbia University College of Physicians and Surgeons, New fragments, including beta-amyloid (A ), the main component York, NY 10032, USA of the amyloid plaques found in AD brains. The fact that e-mail: [email protected] enlarged endosomes represent a cell-biological phenotype of AD has recently been validated in neurons derived from D. Ringe Department of Biochemistry and Chemistry, Rosenstiel Basic patients via induced pluripotent stem cells technology [3]. Medical Sciences Research Center, Brandeis University, Waltham, Endosomes are a hub of membrane trafficking, and mecha- MA 02454, USA nistically it can be assumed that they become enlarged either because of accelerated delivery, via cell-surface endocytosis G. A. Petsko Helen and Robert Appel Alzheimer’s Disease Research Institute, or by reducing the transport of molecules out of endosomes. Weill Cornell Medical College, New York, NY 10065, USA Taken together, these observations establish that endosomal Retromer Chaperones in Alzheimer’sDisease 13 dysfunction is a pathogenic mechanism, and validate takes place; however, many of the studies suggesting a endosomal transport as a “cell biological” target for drug nonendosomal locus of amyloidogenic APP processing have discovery. been performed in experimental conditions that do not resem- As we will discuss below, proteins and mechanisms that ble the normal physiological neuronal state. Nevertheless, one modulate the endosomal residency time of APP, BACE1, and aspect of Aß production is clear: the more time APP and other key molecular players, and hence their physical interac- BACE1 reside and interact with each other in any given tion, could thus regulate the production of Aβ and have cellular compartment under the right conditions (e.g., an acid- implications for AD. One such mechanism is the retromer- ic pH for optimal BACE1 enzymatic activity), the more Aβ is dependent retrieval of transmembrane proteins, such as APP, likely to be produced by the cell. This interplay will be from endosomes to the trans-Golgi network and the plasma determined by the dynamic trafficking routes of each of these membrane. We will begin by looking in some detail at these molecular components separately. While we know that key molecular entities, as their basic biology is important to retromer regulates APP trafficking, less is known about the further understand their roles in neuronal AD-related role of retromer affecting BACE1 transport. BACE1 also retromer-mediated trafficking. shuttles between different membranous subcellular compart- APP is a type I transmembrane protein that can undergo ments [9], hence raising the critical, and still unanswered, proteolytic processing in different ways by different sets of question of how both these important AD molecular players enzymes—in normal healthy conditions, a minor pathway come in closer contact and trigger amyloid-related AD leads to amyloid plaque formation (the amyloidogenic path- pathophysiology. way), while the other major pathway does not (the Another key player in the regulation of APP processing at nonamyloidogenic pathway). In the nonamyloidogenic path- the endosomal level is a sorting protein-related receptor con- way, APP is cleaved first by α-secretase to yield a soluble taining low-density lipoprotein receptor class A repeats N-terminal fragment (sAPPα) and a C-terminal fragment (SorLA). Like APP, SorLA is a type I transmembrane protein (αCTF). The sAPPα fragment may be involved in the that is expressed in neurons and is a critical participant in the enhancement of synaptogenesis, neurite outgrowth, and neu- intracellular transport and processing of APP. Through its ronal survival, and is considered to be neuroprotective [4]. In Vps10-like structural similarity, SorLA binds to the retromer the amyloidogenic pathway, APP is cleaved first by BACE1 complex and serves as an adaptor protein for the trafficking of (a transmembrane aspartic protease), yielding a soluble APP from endosomes to the TGN [10]. It has been shown that N-terminal fragment (sAPPβ) and a membrane-bound SorLA levels are reduced in affected brain areas in patients C-terminal fragment (βCTF). βCTF is then acted upon by with AD [10], and that overexpression of SorLA redistributes γ-secretase yielding a membrane-bound C-terminal fragment APP to the Golgi apparatus thereby reducing the residency and a soluble N-terminal fragment, Aβ.Aβ can then accu- and interaction time of APP and BACE1 in the early mulate in the extracellular space of the brain, where it can endosomes. Consequently, Aβ levels are decreased in SorLA form oligomers, insoluble fibrils, and amyloid plaques if overexpression conditions. These findings became more rele- they are insufficiently cleared, as observed in advanced AD. vant when variants in SORL1 (coding for SorLA) associated The progression to AD is thus determined by the proportion with late-onset AD were identified a few years ago [11]. of APP that is processed by the pathways initiated by The retromer complex was first identified in yeast, medi- BACE1 (i.e., amyloidogenic) and α-secretases (i.e., ating the retrieval of the acid hydrolase receptors from nonamyloidogenic). APP is constitutively actively sorted endosomes (vacuoles in yeast) to the Golgi apparatus [12]. and trafficked through membrane compartments of the cell. Further studies showed that the function and components of After internalization from the cell surface and while it tempo- the retromer complex is evolutionary conserved across spe- rarily resides in endosomes, APP is most likely to interact and cies. Retromers are heteropentameric protein complexes com- be cleaved by BACE1 [5]. Previous studies have shown that posed mainly of 2 components: 1) a structural component retromer-related defects reduced trafficking of APP out of made of a dimer of sorting nexins (SNX), which mediates endosomes and caused an elevation in Aβ levels in vivo the binding to lipids in the endosomal membrane; and 2) a [6, 7]. That said, a recent study performed on HEK293 cells core cargo recognition element, a heterotrimer comprised of using an RNA interference approach suggests that Aβ40 is ‘vacuolar protein sorting’ (VPS) proteins Vps35–Vps29– generated predominantly in the TGN [8]; however, in this case Vps26. Vps35 is the core component of the complex, which no other APP proteolytic fragments were studied. Yet another
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