Studies On Strengthened Glial Clearance Of Beta-Amyloid

Alzheimer’s disease (AD), the most prominent cause of senile dementia,is a neurodegenerative disease which characterized by memory loss andextracellular deposits of fibrillar beta-amyloid (Aβ). Aβ aggregates caninduce oxidative stress, inflammatory cytokine release, calcium turbulence,and apoptosis of neuron. The clearance of Aβ monomer or aggregates is acausal strategy for AD treatment. Microglia and astrocytes are the mainmacrophages that exert critical neuroprotective roles in the brain. They mayeffectively clear the toxic Aβ aggregates at the initial stage of AD. However,their functions are attenuated because of glial overactivation.In this study, we showed that heptapeptide XD4activates the class Ascavenger receptor (SR-A) on the glia by increasing the binding of Aβ toSR-A, thereby promoting glial phagocytosis of Aβ oligomer in microglia andastrocytes and triggering intracellular mitogen-activated protein kinase(MAPK) signaling cascades. Moreover, XD4enhances the internalization ofAβ monomers to microglia and astrocytes through macropinocytosis orSR-A-mediated phagocytosis. Furthermore, XD4significantly inhibits Aβoligomer-induced cytotoxicity to glial cells and decreases the production ofproinflammatory cytokines, such as TNF-α and IL-1β. Our findings mayprovide a novel strategy for AD treatment by activating SR-A.