Regulation of neuroinflammation with GLP-1 receptor targeting nanostructures to alleviate Alzheimer's symptoms in the disease models

The neuroinflammation induced by amyloid-β (Aβ) has emerged as an important role in onset and progression of Alzheimer's disease (AD). Hence, regulating the inflammatory mediators produced by glial cells is valuable for AD treatment. Here we developed a glucagon-like peptide 1 receptor (GLP-1R) agonist with blood-brain barrier (BBB) crossing capability to suppress inflammation induced by microglia and astrocyte. Liraglutide (LRGT) was decorated with angiopep-2 peptide and assembled with polyethylene glycol (PEG) to form a nanostructure (pALRGT), showing a higher brain accumulation than free LRGT. Treatment with pALRGT nanostructures could inhibit the secretion of pro-inflammatory cytokines from the activated microglia through PI3K-AKT/NF-κB pathways. Meanwhile, pALRGT nanostructures promoted the differentiation of astrocytes into protective A2 type and secreted IL-3 for Aβ peptide clearance. Consequently, pALRGT nanostructures significantly alleviated the progression of Aβ peptide induced AD in mice. This study demonstrates a novel strategy to modulate microglia activation and astrocyte reactivity for alleviating the progression of AD.