RECENTLY FOUND IN BRAIN CELLS, COMPLEMENTSTANDS ARRAIGNED OF COMPLICITY IN ALZHEIMER'S
By David N. LeffScience Editor
BOSTON _ A band of outlaws? A sheriff's posse? Both oppositesfit the body's complement cascade.
This string of nine super-proteins acts as the immune system'senforcer. It punches holes in invading bacteria that cause infections,or in the innocent bystander cells of autoimmune diseases, forexample. (See BioWorld Today, May 24, 1993, p. 5.)
Now it looks as if beta-amyloid, the hallmark protein of senileplaques in Alzheimer's disease (AD), secretly recruits the brain'scomplement proteins to kill off neurons and bring on dementia.
Such is the rationale presented here Tuesday by immunologist Suio-Ling Chen to a conference on "Controlling the Complement System,"sponsored by International Business Communications. Chen is ascientist in the discovery group of Cleveland-based Gliatech Inc.
"The hypothesis that complement activation causes neuronal damageand death in Alzheimer's disease," Chen told her audience of about110, "is supported by the observation that complement activationproducts are found co-localized with senile plaques."
As further evidence, she pointed out that "the membrane-damagingterminal complement activation product, MAC, is found associatedwith dystrophic neurites" near those plaques.
The trip wire that tips over the first super-protein in complement'snine-domino cascade is usually an antibody-antigen reaction. Chenreasoned that because antibodies don't appear in the neighborhood ofplaques, "other molecules" must be guilty of triggering the cascade.She noted that "Complement expression is increased in AD [and that]MAC are found associated with dystrophic neurites near senileplaques."
She suggested, "If we can stop the complement activationspecifically, maybe we can stop progression of the disease." In vitroexperiments at Gliatech confirmed that beta-amyloid protein canindeed activate complement in the test tube.
Looking In The Cascade For Inhibitors Thereof
The nine components of the classical complement cascade arenumbered, like license plates, from C1 to C9, with small lettersidentifying the proteins comprising each super-protein.
In search of an activation inhibitor, Chen found that the first 42amino acids of amyloid-beta bind tightly to C1q, the cascade'sstarting pistol. C1q consists of six subunits of three polypeptideseach.
"We found," Chen reported to the meeting, "that a peptide 11 amino-acids long on that A chain of C1q inhibited both amyloid-beta- andDNA-induced complement activation." Based on this data, she stated,"a series of compounds were synthesized with the goal of preventingamyloid-induced initiation of the classical complement cascade, andprototype inhibitors synthesized."
The resulting proprietary small fragments, Chen said, have beensynthesized by Gliatech.
That company's research director, neural chemist Kurt Brunden, toldBioWorld Today, "To date, we have four small non-peptidicmolecules in the range of 400 to 600 molecular weight." HisAlzheimer's program is now at the stage of testing these prototypecomplement-inhibiting fragments for their ability to pass the blood-brain barrier.
Brunden said that Gliatech is seeking a research collaboration with alarger company to pursue the AD-complement connection, beginningwith in vivo testing in animals. The aim is to develop a complementinhibition pill, taken orally, to offer prospective future AD patientsthe incentive to commence prophylactic therapy earlier rather thanlater in life.
Chen observed, "When you have complement interaction in the brain,in AD, I think everybody will agree it's not a desirable thing."
Gliatech's specific strategy, Chen explained, "is to only disrupt beta-amyloid interaction with the complement system at a very early stagein the complement activation, so that the other functions ofcomplement _ as in fighting infection _ remain intact, with itsactivation taken care of by the immune system."
Brunden added that he understands other laboratories are researchinginhibition of later stages in the cascade. This, he fears, may welltrigger harmful systemic activation of the whole-body complementsystem.
Complementologist Scott Barnum, who teaches microbiology andimmunology at the University of Alabama, Birmingham, toldBioWorld Today, "As Dr. Chen's inhibitors are small peptides, it maybe quite possible to get them across the blood-brain barrier into thesurrounding tissues, hopefully inhibit complement, and reduce someof the inflammation that the AD patients have. I think it's areasonable approach."
He bemoaned the lack of a suitable animal model for studying AD,such as those that exist for MS, and observed, "Obviously it's hard toget a human being to say, 'You can take a look at my brain before itgets too far along compared to somebody who is more demented thanI am.'
"Our group has recently been able to find," Barnum reported to theconference, "that in MS, several of the complement system'schemotactic receptors _ which allow cells to move in response tospecific signals _ are markedly enhanced in expression. This effectwaxes and wanes as the disease exacerbates or remits."
Barnum added, "We already have some data suggesting whatregulates the expression of these receptors. We think that in general ithas a value for underlying inflammatory processes, whether it be inMS or AD or neurotraumas _ any type of inflammatory event.
Complement In Brain Is No Respecter Of Diseases
He also recalled that "traditionally, the brain was not a tissueconsidered to be a site of complement production. In the last fiveyears or so, work in our lab and by others has shown that in fact thebrain is a major site of complement synthesis. This strongly suggeststhat complement activity goes to any inflammatory event in the brain,regardless of disease."
Barnum described to the meeting work he is doing with transgenicmice developed by neuropharmacologist Iain Campbell at the ScrippsClinic in La Jolla, Calif. "His group has developed some veryinteresting transgenic mice, in which only their brains overexpressspecific cytokines, including interleukin-6."
Barnum clearly identified certain cell types in these murine brainsthat expressed the C3 complement component. Among them areependymal cells, which line the ventricles of the brain, wherecerebral spinal fluid (CSF) is made, and whence it flows around thebrain and down the spinal cord.
"So that may be the cell," Barnum concluded, "that produces at leastC3, and perhaps other complement proteins normally found at verylow levels in CSF." n
(c) 1997 American Health Consultants. All rights reserved.