High mobility group box-1 (HMGB1) contributes to the MARCKS phosphorylation via Toll-like receptor 4 (TLR4) since blockade of HMGB1–TLR4 binding with monoclonal anti-HMGB1 antibodies suppresses the phosphorylation of MARCKS at Ser46, stabilizes dendritic spines, and rescues cognitive impairment in AD model mice22. Here, TLR4 is linked to Cognitive impairment.