Extracellular matrix glycation epigenetically regulates brain aging and neurodegeneration in the in vitro aged neurovascular model

Advanced glycation end-products (AGEs) accumulate in brain tissue with as we age, co-localizing with amyloid ß and tau in the brains of elderly and Alzheimer's disease patients. However, the link between increased AGE levels, aging, and neurodegeneration remains unclear. To explore the effect and mechanism of AGEs on the brain, we developed a neurovascular (NV) model that reflects features of an aged brain by integrating an AGE-anchored matrix. Notably, we discovered that targeting AGE and its receptor could attenuate AGE-mediated neurodysfunction through the histone-modifying enzyme, KMT2A, in neurons within an aged NV model. Overall design: To investigate the AGE-mediated neurodegenerative mechanism, neuronal cells differentiated from neural progenitor cell lines (ReNcell) were 3D cultured in collagen and Matrigel hydrogel, and provided aged conditions by using soluble AGE and AGE-anchored glycated matrix. We developed RAGE-depleted and -overexpressed ReNcells using shRNA and CRISPR/Cas9, respectively, for further clear mechanistic validation.