Therapeutic efficacy of synthetic analogues of gut hormones in a mouse model of Alzheimer’s disease

Alzheimer's disease (AD) is a neurodegenerative condition characterised by amyloid-β pathology, neuroinflammation, synaptic dysfunction and cognitive decline. Few pharmacological interventions are available, offering only symptomatic relief, and approval for a number of anti-amyloid biologics is limited, with concerns about safety, cost and efficacy. Here we investigated the effects of 8-10 weeks treatment with liraglutide, NAcGIP[Lys(37)PAL] and Xenin-25[Lys(13)PAL], long-lasting analogues of gut hormones glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic peptide (GIP) and xenin-25, respectively, in the APP/PS1 mouse model of AD. Cognitive function was measured in novel object recognition (NOR) and Morris water maze (MWM) tasks and amyloid burden, gliosis, synapse density and neurogenesis were assessed in brains of APP/PS1 and wild-type mice. AD-associated gene expression analysis was performed to identify potential pathways targeted by treatment. Liraglutide and NAcGIP[Lys(37)PAL] improved cognitive performance in APP/PS1 mice and, along with Xenin-25[Lys(13)PAL], reduced amyloid-β burden in the brain. Liraglutide ameliorated gliosis and all three treatments restored synaptophysin levels. Additionally, Xenin-25[Lys(13)PAL] increased neurogenesis in the dentate gyrus. Numerous AD-associated genes were altered in the brain following treatments. Notably, Serpina3c was upregulated in brains of APP/PS1 mice treated with liraglutide, NAcGIP[Lys(37)PAL] and Xenin-25[Lys(13)PAL], while Map2, Adam9, Lrp8, Casp3, Abca1 and App were downregulated. These results underscore the neuroprotective effects of liraglutide and suggest that NAcGIP[Lys(37)PAL] and Xenin-25[Lys(13)PAL] possess neuroprotective properties. Further investigation of the precise nature of these effects may support development of multi-target therapeutics based on combinations of gut hormone analogues.