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Volume 16, Number 19,
Issue of October 1, 1996
pp. 6021-6037
Copyright ©1996 Society for Neuroscience
Specific Domains of  -Amyloid from Alzheimer Plaque Elicit
Neuron Killing in Human Microglia
Received May 22, 1996; revised July 9, 1996; accepted July 10, 1996.
Dana Giulian1,
Lanny J. Haverkamp1,
J. H. Yu1,
William Karshin1,
D. Tom1,
Jun Li1,
Joel Kirkpatrick2,
Y.-M. Kuo3, and
A. E. Roher3
1 Alzheimer's Disease Research Center, Department of
Neurology, Baylor College of Medicine, Houston, Texas 77030, 2 Alzheimer's Disease Research Center, Department of
Pathology, Baylor College of Medicine and The Methodist Hospital,
Houston, Texas 77030, and 3 Halderman Laboratory for
Alzheimer's Disease Research, Sun Health Research Institute, Sun City,
Arizona 85351
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 1-40 or A1-42 peptides, elicited neurotoxin release from
microglia. Screening of various synthetic peptides (A1-16, A1-28,
A12-28, A25-35, A17-43, A1-40, and A1-42) confirmed that
microglia killed neurons only after exposure to nanomolar
concentrations of human A1-40 or human A1-42, whereas the rodent
A1-40 (5Arg Gly, 10TyrPhe,
13HisArg) was not active. These findings
suggested that specific portions of human A were necessary for
microglia-plaque interactions. When coupled to microspheres,
N-terminal portions of human A (A1-16, A1-28, A12-28)
provided anchoring sites for microglial adherence whereas C-terminal
regions did not. Although itself not toxic, the 10-16 domain of human
A 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.
Key words:
Alzheimer's disease;
microglia;
-amyloid;
neurotoxicity;
plaques;
immune system
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