Giving mice a nasal spray of a strong IGF‑1 version (LR3‑IGF‑1) changed the shape of Alzheimer‑related plaques in the brain and made the mice a bit leaner, but it didn’t help them think better or remember things. The drug helped break down harmful small amyloid pieces and made plaques look more inert, yet memory stayed the same.

Insulin-like growth factor-1 (IGF-1) promotes neurogenesis, cell survival, and glial function, making it a promising candidate therapy in Alzheimer's disease (AD). Long arginine 3-IGF-1 (LR3-IGF-1) is a potent IGF-1 analogue. We sought to determine whether intranasal (IN) LR3 treatment would delay cognitive decline and pathology in 5XFAD mice. Wildtype and 5XFAD male mice were treated for 7 months (3-10 months of age), with IN LR3-IGF-1 or IN Vehicle (Veh) (n&#x2009;=&#x2009;19-27 mice/group). Behavior, memory, and brain imaging were assessed at 8-9 months of age and tissues collected at 10 months. A comprehensive amyloid-&#x3b2; (A&#x3b2;) profile and other pathologic features were conducted and supportive <i>in vitro</i> stimulation studies in BV-2 microglial cells were also performed. In male 5XFAD mice, IN LR3-IGF-1 treatment improved body composition, but did not significantly alter cognitive symptoms, as assessed by multiple assays. In cortex, LR3 treatment improved some facets of pathology, including a reduction in filamentous plaques, and increase in inert plaques, corresponding with a reduction in low molecular weight A&#x3b2; oligomers. <i>In vitro</i>, uptake of A&#x3b2;_1-42 peptide by BV2 cells was enhanced by LR3-IGF-1, which was also found to promote gene pathways implicated in actin remodeling and endocytosis. LR3 promotes favorable effects on A&#x3b2; plaque remodeling in cortex of male 5XFAD mice but fails to preserve aspects of behavior or memory. While these data do not support LR3 as a monotherapy <i>per se</i>, they do warrant further investigation into its potential for combinatorial formulations aimed at targeting the complexity of AD.