COMPLEMENT-DEPENDENT PROINFLAMMATORY PROPERTIES OF THE ALZHEIMERS-DISEASE BETA-PEPTIDE

Large numbers of neuritic plaques (NP), largely composed of a fibrilla r insoluble form of the beta-amyloid peptide (AP), are found in the hi ppocampus and neocortex of Alzheimer's disease (AD) patients in associ ation with damaged neuronal processes, increased numbers of activated astrocytes and microglia, and several proteins including the component s of the proinflammatory complement system. These studies address the hypothesis that the activated complement system mediates the cellular changes that surround fibrillar A beta deposits in NP. We report that A beta peptides directly and independently activate the alternative co mplement pathway as well as the classical complement pathway; trigger the formation of covalent, eater-linked complexes of A beta with activ ation products of the third complement component (C3); generate the cy tokine-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 neuro nal precursor cells. These findings provide inflammation-based mechani sms to account for the presence of complement components in NP in asso ciation with damaged neurons and increased numbers of activated glial cells, and they have potential implications for the therapy of AD.