Beneficial Effect of a Small Pharmacologic Chaperone on the Established Alzheimer’s Disease Phenotype

Abstract

Background:

The endosomal retromer complex system is a key controller for trafficking of proteins. Downregulation of its recognition core proteins, such as VPS35, is present in Alzheimer’s disease (AD) brain, whereas its normalization prevents the development of AD pathology in a transgenic model with amyloid-β deposits and tau tangles.

Objective:

Assess the effect of targeting VPS35 after the AD pathology and memory impairments have developed.

Methods:

Twelve-month-old triple transgenic mice were treated with a small pharmacological chaperone, TPT-172, or vehicle for 14 weeks. At the end of this period, the effect of the drug on their phenotype was evaluated.

Results:

While control mice had a decline of learning and memory, the group receiving the chaperone did not. Moreover, when compared with controls the treated mice had significantly less amyloid-β peptides and phosphorylated tau, elevation of post-synaptic protein, and reduction in astrocytes activation.

Conclusion:

Taken together, our findings demonstrate that pharmacologic stabilization of the retromer recognition core is beneficial also after the AD-like pathologic phenotype is established.