Modulation of amyloid precursor protein expression reduces ?-amyloid deposition in a mouse model.

ABSTRACT: Proteolytic cleavage of the amyloid precursor protein (APP) generates ?-amyloid (A?) peptides. Prolonged accumulation of A? in the brain underlies the pathogenesis of Alzheimer disease (AD) and is regarded as a principal target for development of disease-modifying therapeutics.Using Chinese hamster ovary (CHO) APP751SW cells, we identified and characterized effects of 2-([pyridine-2-ylmethyl]-amino)-phenol (2-PMAP) on APP steady-state level and A? production. Outcomes of 2-PMAP treatment on A? accumulation and associated memory deficit were studied in APPSW /PS1dE9 AD transgenic model mice.In CHO APP751SW cells, 2-PMAP lowered the steady-state APP level and inhibited A?x-40 and A?x-42 production in a dose-response manner with a minimum effective concentration???0.5?M. The inhibitory effect of 2-PMAP on translational efficiency of APP mRNA into protein was directly confirmed using a 35S-methionine/cysteine metabolic labeling technique, whereas APP mRNA level remained unaltered. Administration of 2-PMAP to APPSW /PS1dE9 mice reduced brain levels of full-length APP and its C-terminal fragments and lowered levels of soluble A?x-40 and A?x-42 . Four-month chronic treatment of APPSW /PS1dE9 mice revealed no observable toxicity and improved animals' memory performance. 2-PMAP treatment also caused significant reduction in brain A? deposition determined by both unbiased quantification of A? plaque load and biochemical analysis of formic acid-extracted A?x-40 and A?x-42 levels and the level of oligomeric A?.We demonstrate the potential of modulating APP steady-state expression level as a safe and effective approach for reducing A? deposition in AD transgenic model mice.

SUBMITTER: Asuni AA 

PROVIDER: S-EPMC4247163 | biostudies-literature | 2014 May

REPOSITORIES: biostudies-literature