ACTIVATION OF 5-HT₄ RECEPTORS AND INHIBITION OF PHOSPHODIESTERASE TYPE 7 SYNERGISTICALLY ENHANCE MEMORY IN ALZHEIMER’S DISEASE MOUSE MODEL

Alzheimer’s disease (AD), the leading cause of dementia, is a multifactorial neurodegenerative disorder with limited therapeutic options. Targeting multiple pathological pathways using low-dose combination strategies may enhance efficacy while reducing dose-dependent side effects. In this context, modulation of the cyclic adenosine monophosphate (cAMP) signaling pathway, a key regulator of synaptic plasticity and memory, represents a promising approach to counteract AD-related cognitive decline.
Given their convergent modulation of cAMP signaling, we hypothesized that combined activation of 5-HT₄ receptors and inhibition of PDE7 would exert complementary pro-cognitive effects. The efficacy of this strategy, administered acutely or chronically (twice a week) using subactive doses of RS67333 (partial 5-HT₄R agonist) and BRL50481 (selective PDE7 inhibitor), was assessed on recognition and working memory in male and female 5xFAD mice. Novel object recognition was tested at 6 months, and spontaneous alternation at 12 months, corresponding to the emergence of recognition and working memory deficits in 5xFAD mice, respectively.
Our results indicate that acute administration of subactive doses of RS67333 (0.25-0.5mg/kg) and BRL50481 (2.5mg/kg) produced synergistic anti-amnestic effects on recognition and working memory, providing preclinical proof of concept for this dual-target strategy. Chronic treatment from 2 months of age also demonstrated synergistic effects on novel object recognition, with no observable side effects. Ongoing analyses aim to determine whether this strategy confers additional neuroprotective effects, focusing on amyloid plaque deposition (Congo red staining) and brain amyloid beta 42 levels.
These findings support dual 5-HT₄R and PDE7 modulation as an innovative approach to prevent memory decline in AD.