Affiliations: [a]
Alzheimer’s Center at Temple, Lewis Katz School of Medicine, Philadelphia, PA, USA
| [b]
Moulder Center for Drug Discovery Research, School of Pharmacy, Temple University, Philadelphia, PA, USA
Correspondence:
[*]
Correspondence to: Domenico Praticò, MD, FCPP, 3500 North Broad Street, MERB suite 1160, Philadelphia, PA 19140, USA. Tel.: +1 215 707 9380; Fax: +1 215 707 2746; E-mail:praticod@temple.edu.
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.
Keywords: Alzheimer’s disease, amyloid-β, pharmacological chaperone, retromer complex, tau protein
