Model of chronic apoE signaling in adult hippocampus. Reelin interacts exclusively with the lipoprotein receptors apoER2 and VLDLR, with a much higher affinity for apoER2. ApoE binds to all lipoprotein receptors and undergoes endocytosis. Chronic apoE4 exposure enhances ERK1/2 activation, likely through interactions with the LRP1 receptor. In contrast, chronic apoE2 and apoE3 expression reduce activation of JNK1/2 and ERK1/2 activation. Together with proper NMDAR function, these changes culminate in alterations in LTP induction with chronic apoE2 isoform expression.