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J. Exp. Med.,
Volume 188, Number 3, August 3, 1998 431-438
-Peptide
By
From the * Department of Immunology, The Scripps Research Institute, La Jolla, California 92037;
and Large numbers of neuritic plaques (NP), largely composed of a fibrillar insoluble form of the
Advanced Research Technologies, Inc., San Diego, California 92121
-amyloid peptide (A), are found in the hippocampus and neocortex of Alzheimer's disease (AD) patients in association with damaged neuronal processes, increased numbers of activated
astrocytes and microglia, and several proteins including the components of the proinflammatory complement system. These studies address the hypothesis that the activated complement
system mediates the cellular changes that surround fibrillar A deposits in NP. We report that
A peptides directly and independently activate the alternative complement pathway as well as
the classical complement pathway; trigger the formation of covalent, ester-linked complexes of
A with activation products of the third complement component (C3); generate the cytokine-like C5a complement-activation fragment; and mediate formation of the proinflammatory
C5b-9 membrane attack complex, in functionally active form able to insert into and permeabilize the membrane of neuronal precursor cells. These findings provide inflammation-based mechanisms to account for the presence of complement components in NP in association with
damaged neurons and increased numbers of activated glial cells, and they have potential implications for the therapy of AD.
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