Design, synthesis, and investigation of anti-Alzheimer's activity and molecular mechanisms of phosphatidylserine derivatives

Although phosphatidylserine (PS) mixtures exhibit neuroprotective properties, the development of PS-based Alzheimer's disease (AD) therapeutics has been constrained by incomplete structure-activity relationship (SAR) data and poorly defined mechanisms. Herein, 34 novel PS derivatives were designed, synthesized, and evaluated for neuroprotective effects in vitro and in vivo. Most compounds exhibited excellent safety with IC₅₀ values greater than 200 μM in normal cells and potent in vitro neurotrophic activity, exemplified by A18, which enhanced neuronal proliferation (increased by 29.4 ± 3.3%), rescued rotenone-injured neurons (cell survival increased by 42.5 ± 1.9%), and promoted synaptogenesis in primary neurons. Synaptogenesis was quantified by an increase of MAP2-positive neurite length (42.0 ± 2.3 μm in A18-treated neurons vs. 27.6 ± 2.9 μm in the control group, ∗∗p < 0.01), with further synergistic effects observed when combined with Neurotrophin Growth Factor (NGF). In Aβ_1-42-induced AD mice, A18 (25 mg/kg/day) demonstrated multimodal efficacy: restoring spatial memory(as evidenced by an increase in platform crossings, ∗∗∗∗p < 0.0001), preserving synaptic ultrastructure, and reducing neuroinflammation (decreasing TNF-α/IL-6 levels by 40-60%, ∗p < 0.05). Mechanistic studies have revealed that A18 activates the PI3K/Akt and ERK-CREB signaling pathways while suppressing neuroinflammatory pathways. Critical SAR principles establish para-benzoates with nitro groups (e.g., A18) as optimal pharmacophores and glycerol backbone integrity as essential. These findings provide a foundation for future PS-based AD drug development.

Alzheimer's disease; Morris water maze; Neurogenic; Neuroprotective effects; Phosphatidylserine.