Specific domains of beta-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 A beta 1-40 or A beta 1-42 peptides, elicited neurotoxin release from microglia. Screening of various synthetic peptides (A beta 1-16, A beta 1-28, A beta 12-28, A beta 25-35, A beta 17-43, A beta 1-40, and A beta 1-42) confirmed that microglia killed neurons only after exposure to nanomolar concentrations of human A beta 1-40 or human A beta 1-42, whereas the rodent A beta 1-40 (5Arg-->Gly, 10Tyr-->Phe 13His-->Arg) was not active. These findings suggested that specific portions of human A beta were necessary for microglia-plaque interactions. When coupled to microspheres, N-terminal portions of human A beta (A beta 1-16, A beta 1-28, A beta 12-28) provided anchoring sites for microglial adherence whereas C-terminal regions did not. Although itself not toxic, the 10-16 domain of human A beta 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.
Giulian
D
D
Alzheimer's Disease Research Center, Department of Neurology, Baylor College of Medicine, Houston, Texas 77030, USA.
Haverkamp
L J
LJ
Yu
J H
JH
Karshin
W
W
Tom
D
D
Li
J
J
Kirkpatrick
J
J
Kuo
L M
LM
Roher
A E
AE
D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000235:genetics* / Q000378:metabolism* / Q000502:physiology; D000818:Animals; D002450:Cell Communication; D006801:Humans; D017628:Microglia / Q000502:physiology*; D009474:Neurons / Q000502:physiology*; D009498:Neurotoxins / Q000494:pharmacology; D010446:Peptide Fragments / Q000502:physiology; D051381:Rats
D016229:Amyloid beta-Peptides; D009498:Neurotoxins; D010446:Peptide Fragments