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

Abstract

Objective 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’s disease (AD) and is regarded as a principal target for development of disease-modifying therapeutics. Methods Using 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. Results In CHO APP751SW cells, 2-PMAP in a dose-response manner lowered the steady-state APP level and inhibited Aβx-40 and Aβx-42 production with minimum effective concentration ≤0.5μM. The inhibitory effect of 2-PMAP on translational efficiency of APP mRNA into protein was directly confirmed using 35S-methionine/cysteine metabolic labeling technique, while 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 along with lowering 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. Interpretation 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.

Beneficial Effects of the β-Secretase Inhibitor GRL-8234 in 5XFAD Alzheimer’s Transgenic Mice Lessen During Disease Progression

“…In recent clinical trial failure of β-secretase inhibitor, it is pointed out that the observed liver toxicity may not necessarily be due to “off-target” (i.e., “off-BACE1) side effects but reflect “off-site” effects (i.e., BACE1 inhibition on β-galactoside α-2,6-sialyltransferase I in liver) that could be masked in animal models [53]. Our results suggest that a combination of the BACE1 inhibitor and agents that block BACE1-elevating pathways [30, 54, 55], lower APP expression [56, 57] or remove Aβ plaques (e.g., passive immunization) [58] may provide a more efficacious and safe strategy to treat memory deficits in AD with established amyloid pathology.…”

Amyloid‐β precursor protein synthesis inhibitors for Alzheimer's disease treatment

“…[1] Unlike outcomes in neuronal cells,[4, 5] we found phenserine relatively inactive using CHO clones (unpublished data). Phenserine is also highly lipophilic (clog P n-octanol/water partition value = 2.22 (vs. 0.925 for 2-PAM) ((i.e., a 160-fold preference for the lipid vs. aqueous phase for phenserine vs. 8-fold for 2-PAM)).…”

“…[1] As the repeated clinical trial failures in AD warn, along with all other AD investigators they now face daunting tasks ahead. Methods and knowledge of AD pathological mechanisms may not be available to successfully time 2-PMAP interventions early enough in the course of AD to prevent possible amyloid β–induced irreversible pathologies such as phosphorylated-tau protein.…”

“…We found it necessary to use the tartrate salt in preclinical/clinical studies to provide reliable aqueous bioavailability. [4] The use by Asuni and colleagues[1] of free base phenserine risks functional concentrations far lower than they reported.…”

Blocking the apoE/Aß interaction ameliorates Aß-related pathology in APOE ¿2 and ¿4 targeted replacement Alzheimer model mice

“…Vehicle treated mice received injections with phosphate buffered saline only. Immediately prior to concluding the study the animals were subjected to behavioral testing conducted following our published protocols [15,19,20]. Age and sex-matched littermates of APP/E2 and APP/E4 mice in which genotyping was negative for the APP SW /PS1 dE9 transgene (hereafter designated as WT/E2 and WT/E4, respectively) were used as an apoE isoform background control during the behavioral and serological testing.…”