Designed macrocyclic peptide rescues behavioral impairment and brain pathology in an Alzheimer’s disease mouse model

Alzheimer's disease (AD) is a neurodegenerative disorder hallmarked by the accumulation of extracellular amyloid-β (Aβ) plaques, with currently limited therapeutic options. We explored the potential of a macrocyclic peptide, 2E, designed to robustly inhibit Aβ self-aggregation by mimicking the interaction surface of islet amyloid polypeptide (IAPP) with Aβ. Our findings from two treatment paradigms in 5XFAD female and male mice revealed a significant reduction in cortical amyloid deposition, decreased neuronal damage, and enhanced astrocytic activation upon 2E administration. Furthermore, treated mice displayed improvements in memory and motor functions without any alterations in anxiety or stress responses, as evidenced by behavioral tests. Notably, RNA-seq analyses highlighted 2E's ability to bolster astrocytic activation while reversing AD-associated neuronal gene expression changes. Importantly, following intraperitoneal injection, 2E's presence in the brain attests to its biodistribution capability. Thus, the macrocyclic peptide 2E, either as a standalone or combined with other anti-amyloid strategies, emerges as a promising candidate to combat Aβ-driven AD pathogenesis. To study the effect of 2E treatment on cellular responses, RNA for bulk RNA-Seq was isolated from PFA-fixed micro-dissected brain tissue from wild-type, saline-treated 5xFAD mice and 2E-treated 5xFAD mice using optimized protocol. Samples were collected from four brain regions (cortex, hippocampus, brain stem, and cortex+hippocampus). RNA-Seq libraries were prepared using SmartSeq2 protocol.