Specific domains of β-amyloid from Alzheimer plaque elicit neuron killing in human microglia

Alzheimer's disease (AD) is found to have striking brain inflammation characterized by clusters of reactive microglia that surround senile plaques. A recent study has shown that microglia placed in contact with isolated plaque fragments release neurotoxins. To explore further this process of immunoactivation in AD, we fractionated plaque proteins and tested for the ability to stimulate microglia. Three plaque-derived fractions, each containing full-length native Aβ1-40 or Aβ1-42 peptides, elicited neurotoxin release from microglia. Screening of various synthetic peptides (Aβ1-16, Aβ1-28, Aβ12-28, Aβ25-35, Aβ17-43, Aβ1-40, and Aβ1-42) confirmed that microglia killed neurons only after exposure to nanomolar concentrations of human Aβ1-40 or human Aβ1-42, whereas the rodent Aβ1-40 (5(Arg-Gly), 10(Tyr-Phe), 13(His -Arg) was not active. These findings suggested that specific portions of human Aβ were necessary for microglia- plaque interactions. When coupled to microspheres, N-terminal portions of human Aβ (Aβ1-16, Aβ1-28, Aβ12-28) provided anchoring sites for microglial adherence whereas C-terminal regions did not. Although itself not toxic, the 10-16 domain of human Aβ was necessary for both microglial binding and activation. Peptide blockade of microglia-plaque interactions that occur in AD might prevent the immune-driven injury to neurons.