The Use of Pharmacological Retromer Chaperones in Alzheimer's Disease and other Endosomal-related Disorders

Abstract

The retromer is an evolutionary conserved multiprotein complex involved in the sorting and retrograde trafficking of cargo from endosomal compartments to the Golgi network and to the cell surface. The neuronal retromer traffics the amyloid precursor protein away from the endosomes, a site where amyloid precursor protein is enzymatically cleaved into pathogenic fragments in Alzheimer's disease. In recent years, deficiencies in retromer-mediated transport have been implicated in several neurological and non-neurological diseases, including Parkinson's disease, suggesting that improving the efficacy of the retromer trafficking pathway would result in decreased pathology. We recently identified a new family of small molecules that appear to stabilize the interaction between members of the retromer complex and enhance its function in neurons: the retromer pharmacological chaperones. Here we discuss the role of these molecules in the improvement of retromer trafficking and endosomal dysfunction, as well as their potential as therapeutics for neurological and non-neurological disorders.

The Role of Retromer in Alzheimer’s Disease

“…These results, which validated the hypothesis, showed that pharmacological chaperones can limit the processing of APP by stabilizing the retromer complex and may have potential therapeutic implications [70]. The retromer pharmacological chaperones are designed to function in the cellular biology and improve APP trafficking by the normal cargo flow toward the Golgi [71]. Studies discovered that increasing retromer levels is relatively nontoxic to mice, yeast, cultured neurons, and flies [71][72][73].…”

“…The retromer pharmacological chaperones are designed to function in the cellular biology and improve APP trafficking by the normal cargo flow toward the Golgi [71]. Studies discovered that increasing retromer levels is relatively nontoxic to mice, yeast, cultured neurons, and flies [71][72][73]. This therapeutic approach may be more effective and requires validation in vivo.…”

“…This therapeutic approach may be more effective and requires validation in vivo. As microglia abnormalities are associated with AD, whether the retromer chaperones would be useful to glia-related trafficking phenotype needs further study [9,71].…”

Analysis of novel endosome-to-Golgi retrieval genes reveals a role for PLD3 in regulating endosomal protein sorting and amyloid precursor protein processing

“…Due to its key function in endosomal protein sorting and prominent role in regulating APP trafficking, there has been considerable interest in retromer as a potential engine of pathogenesis for AD [19, 20], but retromer does not operate in isolation in endosomal protein sorting. We have recently reported the results of a genome-wide siRNA screen for novel endosome-to-Golgi retrieval genes that may function alongside retromer [21].…”

Opposing functions for retromer and Rab11 in extracellular vesicle cargo traffic at presynaptic terminals

“…In cellular and animal models of Alzheimer's Disease, loss of retromer exacerbates synaptic and cognitive defects, and causes mislocalization of APP as well as its amyloidogenic protease BACE1, ultimately leading to increased Ab (Bhalla et al, 2012;Choy et al, 2012;Eggert et al, 2018;Li et al, 2019;Muhammad et al, 2008;Sullivan et al, 2011;Tan and Gleeson, 2019;Wen et al, 2011). Retromer levels are reduced in the entorhinal cortex of Alzheimer's Disease patients (Small et al, 2005), and it has therefore been proposed as a therapeutic target (Berman et al, 2015;Mecozzi et al, 2014). Further, a point mutation (Vps35 D620N ) in human retromer that disrupts interactions with the endosomal actin-regulating WASH complex (Harbour et al, 2010;Jia et al, 2012;Seaman et al, 2013), is linked to Parkinson's Disease and causes neurodegeneration in mice (Chen et al, 2019b;Cui et al, 2018).…”