Neuroprotective Activities of Heparin, Heparinase III, and Hyaluronic Acid on the A β 42-Treated Forebrain Spheroids Derived from Human Stem Cells.

Extracellular matrix (ECM) components of the brain play complex roles in neurodegenerative diseases. The study of microenvironment of brain tissues with Alzheimer's disease revealed colocalized expression of different ECM molecules such as heparan sulfate proteoglycans (HSPGs), chondroitin sulfate proteoglycans (CSPGs), matrix metal-loproteinases (MMPs), and hyaluronic acid. In this study, both cortical and hippocampal populations were generated from human-induced pluripotent stem cell-derived neural spheroids. The cultures were then treated with heparin (competes for A β affinity with HSPG), heparinase III (digests HSPGs), chondroitinase (digests CSPGs), hyaluronic acid, and an MMP-2/9 inhibitor (SB-3CT) together with amyloid β (A β 42) oligomers. The results indicate that inhibition of HSPG binding to A β 42 using either heparinase III or heparin reduces A β 42 expression and increases the population of β -tubulin III+ neurons, whereas the inhibition of MMP2/9 induces more neurotoxicity. The results should enhance our understanding of the contribution of ECMs to the A β -related neural cell death.