Blocking P301S–Kelch‐like ECH‐associated protein 1 (KEAP1) interaction by a custom‐designed peptide attenuates P301S‐induced synapse loss and synaptic protein reduction. (A and B) P2 reversed P301S‐decreased spine density detected by Golgi‐cox staining. One‐way analysis of variance (ANOVA), F(3, 56) = 11.54, p < .0001; n = 15. (C and D) P2 reversed P301S‐impaired neural complexity in the hippocampus by Sholl analysis. Two‐way ANOVA × distance, F(3, 160) = 114.7, p < .0001; n = 5. (E–G) P2 ameliorated P301S‐decreased protein (E and F) and mRNA (G) levels of synaptic proteins. One‐way ANOVA, for panel (F) [KEAP1] F(3, 8) = 7.632, p = .0198; [PSD93] F(3, 8) = 9.645, p = .0046; [PSD95] F(3, 8) = 9.828, p = .0179; [SYN1] F(3, 8) = 8.137, p = .0082, n = 3. For panel (G) [DLG2] F(3, 8) = 5.537, p = .0236; [DLG4] F(3, 8) = 6.705, p = .0142; [SYN1] F(3, 8) = 4.938, p = .0315; n = 3. *p < .05, **p < .01 versus VEC + NP; #p < .05, ##p < .01 versus P301S + NP. Data were presented as mean ± SEM.