Accumulation of extracellular elastin-derived peptides disturbed neuronal morphology and neuron-microglia crosstalk in aged brain

Extracellular elastin-derived peptides (EDPs) accumulate in the aging brain and have been associated with vascular dementia and Alzheimer's disease (AD). The activation of inflammatory processes in glial cells with EDP treatment has received attention, but not in neurons. To properly understand EDPs' pathogenic significance, the impact on neuronal function and neuron-microglia crosstalk was explored further. Among the EDP molecules, Val-Gly-Val-Ala-Pro-Gly (VGVAPG) is a typical repeating hexapeptide. Here, we observed that EDPs-VGVAPG influenced neuronal survival and morphology in a dose-dependent manner. High concentrations of VGVAPG induced synapse loss and microglia hyperactivation in vivo and in vitro. Following EDP incubation, galectin 3 (Gal-3) released by neurons served as a chemokine, attracting microglial engulfment. Blocking Gal-3 and EDP binding remedied synapse loss in neurons and phagocytosis in microglia. In response to the accumulation of EDPs, proteomics in matrix remodeling and cytoskeleton dynamics, such as a disintegrin and metalloproteinase (ADAM) family, were engaged. These findings in extracellular EDPs provided more evidence for the relationship between aging and neuron dysfunction, increasing the insight of neuroinflammatory responses and the development of new specialized extracellular matrix remolding-targeted therapy options for dementia or other neurodegenerative disease. Extracellular elastin fibers were degraded irreversibly in the aging brain, increasing sensitivity to stroke, vascular dementia, and Alzheimer's disease. The role of physiologically active elastin-derived peptides (EDPs) in neurons is currently being studied. It was suggested that release and accumulation of EDPs lead to neuronal spine loss and microglial hyperactivation. Galectin (Gal-3) secretion from stressed neurons was engaged in the neurons-microglia crosstalk, which promoted microglia engulfment. Synapse loss and local neuroinflammatory processes would contribute to neurological symptoms associated with neurodegenerative disorders. Targeting extracellular matrix integrity provides a promising therapeutic strategy for neurodegenerative disease.image