Modulation of Amyloid Precursor Protein Expression Reduces β-Amyloid Deposition in a Mouse Model

Objective: Proteolytic cleavage of the amyloid precursor protein (APP) generates beta-amyloid (A beta) peptides. Prolonged accumulation of A beta in the brain underlies the pathogenesis of Alzheimer disease (AD) and is regarded as a principal target for development of disease-modifying therapeutics. Methods: Using Chinese hamster ovary (CHO) APP(751SW) cells, we identified and characterized effects of 2-([pyridine-2-ylmethyl]-amino)-phenol (2-PMAP) on APP steady-state level and A beta production. Outcomes of 2-PMAP treatment on A beta accumulation and associated memory deficit were studied in APP(SW)/PS1(dE9) AD transgenic model mice. Results: In CHO APP(751SW) cells, 2-PMAP lowered the steady-state APP level and inhibited A beta(x-40) and A beta(x-42) production in a dose-response manner with a minimum effective concentration <= 0.5 mu 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 APP(SW)/PS1(dE9) mice reduced brain levels of full-length APP and its C-terminal fragments and lowered levels of soluble A beta(x-40) and A beta(x-42). Four-month chronic treatment of APP(SW)/PS1(dE9) mice revealed no observable toxicity and improved animals' memory performance. 2-PMAP treatment also caused significant reduction in brain A beta deposition determined by both unbiased quantification of A beta plaque load and biochemical analysis of formic acid-extracted A beta(x-40) and A beta(x-42) levels and the level of oligomeric A beta. Interpretation: We demonstrate the potential of modulating APP steady-state expression level as a safe and effective approach for reducing A beta deposition in AD transgenic model mice.