Therapeutic Potential of HAEEPGP Peptide Against β-Amyloid Induced Neuropathology

The development of effective therapies for Alzheimer's disease remains a critical challenge in modern medicine. While monoclonal antibodies targeting beta-amyloid (Aβ) have shown the most significant clinical efficacy, their use is limited by poor blood-brain barrier permeability and side effects, which are occasionally severe. We previously devised ion-complementary to Aβ tetrapeptide HAEE, that was able to suppress amyloidogenesis in vivo. In this study, we modified HAEE by adding PGP amino acid residues to its C-terminus to improve its pharmacological properties. Pharmacokinetic analysis revealed that the ¹²⁵I-HAEEPGP half-life in mouse plasma was twice that of ¹²⁵I-HAEE and C-terminus modification of HAEE significantly increased its brain tissue penetration. Isothermal titration calorimetry experiments revealed that HAEEPGP formed a stable complex with Aβ and, besides, exhibited higher affinity for pathogenic isomerized Aβ than for the native peptide. ¹²⁵I-HAEEPGP showed enhanced accumulation in the brain of 5xFAD transgenic mice compared to wild-type controls. Furthermore, using western blotting, ELISA, and flow cytometry, we demonstrated that HAEEPGP considerably reduced Aβ-induced astrocyte and microglia activation, prevented synaptic degeneration in 5xFAD mice, and restored lifespan of Caenorhabditis elegans overexpressing human Aβ. These features of HAEEPGP have positioned it as a promising therapeutic candidate for Aβ-related neuropathology.