Abstract
BackgroundThe vacuolar protein sorting 35 (VPS35) is a major component of the retromer complex system, an ubiquitous multiprotein assembly responsible for sorting and trafficking protein cargos out of the endosomes. VPS35 can regulate APP metabolism and Aβ formation, and its levels are reduced in Alzheimer’s disease (AD) brains. We and others demonstrated that VPS35 genetic manipulation modulates the phenotype of mouse models of AD. However, the translational value of this observation remains to be investigated.MethodsTriple transgenic mice were randomized to receive a pharmacological chaperone, which stabilizes the retromer complex, and the effect on their AD-like phenotype assessed.ResultsCompared with controls, treated mice had a significant improvement in learning and memory, an elevation of VPS35 levels, and improved synaptic integrity. Additionally, the same animals had a significant decrease in Aβ levels and deposition, reduced tau phosphorylation and less astrocytes activation.ConclusionsOur study demonstrates that the enhancement of retromer function by pharmacological chaperones is a potentially novel and viable therapy against AD.
Highlights
The vacuolar protein sorting 35 (VPS35) is a major component of the retromer complex system, an ubiquitous multiprotein assembly responsible for sorting and trafficking protein cargos out of the endosomes
In the Y-maze test, we observed that there was no difference in the general motor activities among the four groups of mice, as we found that the drug did not have any influence on the number of entries compared with controls (Fig. 1a)
In the fear conditioning test, we found that compared with wild-type mice (WT), 3xTg mice had a significant decrease in freezing time for the cued, but not the contextual recall phase, and this was rescued in the 3xTg mice treated with the drug (Fig. 1c, d)
Summary
The vacuolar protein sorting 35 (VPS35) is a major component of the retromer complex system, an ubiquitous multiprotein assembly responsible for sorting and trafficking protein cargos out of the endosomes. VPS35 is the most important component of the cargo recognition core module of the retromer complex system, a ubiquitous multiprotein assembly whose main function is the trafficking of cargo proteins from the endosomes to the trans-Golgi or the cell plasma membrane [4]. Retromer complex dysfunction (2020) 15:1 and decrease in pathological tau [9] Taken together this evidence strongly supports a functional involvement of VPS35 and the retromer complex system in AD pathogenesis. Whether this major component of the recognition core module is a potential target for pharmacological intervention in vivo remains to be investigated
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