Modulation of amyloid precursor protein expression reduces β‐amyloid deposition in a mouse model

Abstract

Proteolytic cleavage of the amyloid precursor protein (APP) generates β-amyloid (Aβ) peptides. Prolonged accumulation of Aβ 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 Aβ production. Outcomes of 2-PMAP treatment on Aβ 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 Aβx-40 and Aβx-42 production in a dose-response manner with a minimum effective concentration ≤ 0.5μM. 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 Aβx-40 and Aβx-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 Aβ deposition determined by both unbiased quantification of Aβ plaque load and biochemical analysis of formic acid-extracted Aβx-40 and Aβx-42 levels and the level of oligomeric Aβ. We demonstrate the potential of modulating APP steady-state expression level as a safe and effective approach for reducing Aβ deposition in AD transgenic model mice.