The Role of Retromer in Alzheimer’s Disease

Abstract

The retromer complex is an important component of the endosomal protein sorting machinery and mediates protein cargoes from endosomes to the trans-Golgi network (TGN) by retrograde pathway or to the cell surface through recycling pathway. Studies show that retromer and its receptors can make amyloid precursor protein (APP)/β-site APP-cleaving enzyme 1 (BACE1) away endosomes that reduces the production of amyloid β (Aβ). And, tetramer is also found to regulate phagocytic receptors to the plasma membrane of microglia, where some phagocytic receptors take part in Aβ clearance. Therefore, disruption of retromer will increase the production of Aβ. Recently, a plausible relationship between disturbance of retromer and tauopathies is raised. Retromer dysfunction may result in decreasing the clearance of extracellular tau and the level of cathepsin D, which enables tau-induced neurotoxicity. This review article summarizes the structure and function of retromer and its role in pathogenesis of AD. In the end, retromer may provide a potential therapeutic strategy for the treatment of AD.

Mitochondrial Dysfunction, Oxidative Stress, and Neuroinflammation: Intertwined Roads to Neurodegeneration

“…The endosomal compartment is also a hub for the intracellular trafficking of APP by hosting the activity of the β-site APP-cleaving-enzyme, which is involved in amyloid plaque generation [ 93 ]. Indeed, a retromer complex is operative to allow retrograde transport of APP from endosomes to the trans Golgi network and reduces A β production [ 94 ]. Instead, impaired retromer complex activity has been involved in AD pathogenesis [ 94 ].…”

“…Indeed, a retromer complex is operative to allow retrograde transport of APP from endosomes to the trans Golgi network and reduces A β production [ 94 ]. Instead, impaired retromer complex activity has been involved in AD pathogenesis [ 94 ].…”

RAB10: an Alzheimer’s disease resilience locus and potential drug target

“…The retromer complex consists of Vps26, Vps35, Vps29, SNX1, SNX2, SNX5, and SNX6 59. The retromer complex regulates transport of protein cargo from endosomes to the TGN by the retrograde pathway or to the cell surface through the recycling pathway 60…”

“…The β-CTF fragments are then trafficked via retromer-dependent transport to the TGN, which facilitates further cleavage by γ-secretase to produce Aβ40 63. The retromer complex and its receptors can transport APP and BACE1 from endosomes to the TGN, ultimately regulating production of Aβ 60. The retromer complex sorts APP and BACE, either through direct or indirect binding to the transmembrane adaptor protein SORLA 64.…”

Vps35 Deficiency Impairs Cdk5/p35 Degradation and Promotes the Hyperphosphorylation of Tau Protein in Retinal Ganglion Cells

“…V acuolar protein sorting 35 (Vps35) functions as a core subunit of the retromer. The Vps35/retromer orchestrates the endosome-to-cell surface, endosome-to-Golgi, and mitochondria-to-peroxidase retrieval of membrane proteins, which plays an important role in neurodegenerative diseases, such as Alzheimer's disease 1,2 and Parkinson's disease. [3][4][5] The hyperphosphorylation of tau protein is known to be pivotally involved in the etiopathogenesis of neurodegenerative diseases.…”