ISOFORM-SPECIFIC INTERACTIONS OF APOLIPOPROTEIN-E WITH MICROTUBULE-ASSOCIATED PROTEIN TAN - IMPLICATIONS FOR ALZHEIMER-DISEASE

The apolipoprotein E (apoE) type 4 allele (APOE4) is a susceptibility gene for late-onset familial and sporadic Alzheimer disease. ApoE is f ound in some neurofibrillary tangle-bearing neurons, one of the major pathologic hallmarks of the disease. Neurofibrillary tangles contain p aired helical filaments formed from hyperphosphorylated microtubule-as sociated protein tan. In vitro, tau binds avidly to apoE3, but not to apoE4, forming a bimolecular complex. Tau phosphorylated with a brain extract does not bind either isoform. ApoE3 binds to the microtubule-b inding repeat region of tau, which is also the region that is thought to cause self assembly into the paired helical filament. Binding studi es with fragments of ApoE demonstrate that the tau-binding region of a poE3 corresponds to its receptor-binding domain and is distinct from t he region that binds lipoprotein particles or beta/A4 peptide. Isoform -specific interactions of apoE with tau may regulate intraneuronal tau metabolism in Alzheimer disease and alter the rate of formation of pa ired helical filaments and neurofibrillary tangles.