RA-PR058, a novel ramalin derivative, reduces BACE1 expression and phosphorylation of tau in Alzheimer’s disease mouse models

Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder characterized by cognitive decline, anxiety-like behavior, β-amyloid (Aβ) accumulation, and tau hyperphosphorylation. BACE1, the enzyme critical for Aβ production, has been a major therapeutic target; however, direct BACE1 inhibition has been associated with adverse side effects. This study investigates the therapeutic potential of RA-PR058, a novel ramalin derivative, as a multi-targeted modulator of AD-related pathologies. The effects of RA-PR058 were evaluated <i>in vitro</i> and <i>in vivo</i>. <i>In vitro</i> studies used SH-SY5Y cells under oxidative stress conditions to assess BACE1 expression, while <i>in vivo</i> effects were studied in 3xTg-AD mice following one month of oral RA-PR058 treatment. Behavioral assessments, biochemical analyses, transcriptomic profiling, and pharmacokinetic evaluations were performed to determine the efficacy of RA-PR058. RA-PR058 significantly reduced oxidative stress-induced BACE1 expression <i>in vitro</i> and decreased cortical BACE1 expression in 3xTg-AD mice. <i>In vivo</i> treatment alleviated anxiety-like behavior and reduced tau phosphorylation at disease-relevant sites (Ser202/Thr205, Thr231, and Ser396). Transcriptomic analysis revealed RA-PR058-mediated gene expression changes related to central nervous system development, response to hypoxia, and neuroactive ligand-receptor interactions, suggesting broader regulatory effects on AD-related pathways. Pharmacokinetic analysis demonstrated that RA-PR058 exhibits high metabolic stability, minimal cytochrome P450 interactions, and moderate blood-brain barrier penetration. RA-PR058 demonstrates potential as a multi-target AD therapeutic by reducing BACE1 expression, tau hyperphosphorylation, and anxiety-like behavior, coupled with favorable pharmacokinetics. Additional studies are needed to assess cognitive effects and clarify molecular mechanisms, but RA-PR058 may represent a promising advancement in addressing AD's complex pathology.