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.