A pharmacological chaperone improves memory by reducing A[beta] and tau neuropathology in a mouse model with plaques and tangles

Background 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 can regulate APP metabolism and A[beta] formation, and its levels are reduced...

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Published inMolecular neurodegeneration Vol. 15; no. 1
Main Authors Li, Jian-Guo, Chiu, Jin, Ramanjulu, Mercy, Blass, Benjamin E, Praticò, Domenico
Format Journal Article
LanguageEnglish
Published BioMed Central Ltd 22.01.2020
Subjects
Advertising executives
Alzheimer's disease
Analysis
Diseases
Genetic engineering
Memory
Novels
Physiological aspects
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Summary:Background 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 can regulate APP metabolism and A[beta] 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. Methods Triple transgenic mice were randomized to receive a pharmacological chaperone, which stabilizes the retromer complex, and the effect on their AD-like phenotype assessed. Results Compared 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 A[beta] levels and deposition, reduced tau phosphorylation and less astrocytes activation. Conclusions Our study demonstrates that the enhancement of retromer function by pharmacological chaperones is a potentially novel and viable therapy against AD. Keywords: Alzheimer's disease, Transgenic mice, Retromer complex, Amyloid beta, tau protein, Therapeutics
ISSN:1750-1326
1750-1326
DOI:10.1186/s13024-019-0350-4