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THE LANCET Neurology Vol 2 June 2003 http://neurology.thelancet.com330

Soluble amyloid oligomers: a commoncause of neurodegeneration?

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The soluble amyloid oligomers thathave been identified in Parkinson’s,Huntington’s, and Alzheimer’sdiseases, prion-related disorders, andtype II diabetes share a three-dimensional structure and are allrecognised by an antibody specific tomicellar amyloid-� peptide (A�),according to new research. “The factthat this epitope is common toamyloids of widely varying primarysequence indicates that the epitope isformed from a specific conformationof the polypeptide backbone and islargely independent of the amino-acid side chains in this region”,observes senior author Charles Glabe(University of California, Irvine, CA,USA).

Glabe’s group focused on thesoluble amyloid oligomers that arefound in Alzheimer’s disease. Theseare a mixture of spherical particles,2·7–4·2 �m in diameter, and proto-fibrils (short strings of the spheresstrung together). In Alzheimer’sdisease, the distribution of theseinclusions in the brain correlatesbetter with the severity of symptomsthan the distribution of definiteplaques. The current theroy is that these soluble intermediates may be more important for diseasepathogenesis than the fully-formedfibrillar amyloid in insoluble plaques.

The group synthesised a moleculethat mimics the three dimensionalstructure of this spherical form of A�and used this to immunise rabbits.The resulting antisera, althoughpolyclonal, was very specific for thesoluble amyloid; it did not recognise

either low molecular weight A� orfibrils. “Surprisingly, we also foundthat the oligomer-specific antibodyreacts well with all of the solubleoligomeric aggregates, regardless ofsequence, including oligomeric andprotofibrillar aggregates from �-synuclein, islet amyloid polypep-tide, polyglutamine, lysozyme,human insulin, and prion peptide”,says Glabe. Furthermore, the toxicityof soluble A� oligomers in an assaywith human neuroblastoma cells wasreduced by incubation for 30 minwith oligomer-specific antibody(Science 2003; 300: 486–89).

Mary Jo LaDu (EvanstonNorthwestern Healthcare ResearchInstitute, IL, USA) comments thatthe development of a polyclonalantibody specific to non-fibrillar A� is a major advance as a research,and potential therapeutic, tool. “That it is not specific to a singleamyloid-forming peptide is evenmore intriguing”, she says. Andreas Modler (Biopolymerphysics, Berlin,Germany) agrees and says that if these findings are confirmed, “this study will mark a majorbreakthrough in the diagnosis ofneurodegenerative diseases”. Hethinks oligomers may be a commonfactor in the pathogenesis of differentdiseases, but cautions that it is too early to be sure. “Nevertheless, I think that it should now be possible to design an early diagnostictest and to develop better assays for drug development”, heconcludes.Kathryn Senior

injection. After 45 days, from a state of hind-limb paralysis, the miceimproved to either full recovery (27%by either injection route) or recoverywith some minor, remnant tailparalysis (73%).

“This work shows it might really bepossible to use somatic neural stem celltherapy to regenerate nervous tissue in

multifocal neurological diseases”, says Miguel Torres (National Bio-technology Center, Madrid, Spain).

“We are now going to try the sameapproach in a non-human primatemodel of MS”, says Martino. “Wehope to have the first results by theend of 2004.”Adrian Burton

Neural precursor cells injected intomice with experimental autoimmuneencephalomyelitis (EAE)—a murinemodel of multiple sclerosis (MS)—canmigrate to multiple damage sites,induce remyelination, and even bringabout recovery, Italian researchersreport (Nature 2003; 422: 688–94).

In MS, the immune systemmistakenly attacks the myelin thatsurrounds neurons, gradually causingparalysis, blindness, and even death.Currently, the best way to ward offfurther deterioration is with immuno-suppressant drugs, but these newfindings suggest that the CNS canactually be repaired.

Stefano Pluchino and colleagues(San Raffaele Hospital, Milan, Italy)grew adult neural stem cells from theperiventricular zone of mice andinjected them either intravenously orintracerebroventricularly into micewith EAE. 10 days later, the injectedcells were found along the entireneuraxis. By 30 days, many had entereddeep into the brain parenchyma,mostly to sites showing demyelinationand axonal loss: in effect, they had goneto where they were most needed. “Thiswas due to the presence of VLA-4 [anadhesion molecule that helps stem cells,and immune system cells, cross theblood–brain barrier in inflammatorysituations] on the surface of thesecells”, explains team leader GianvitoMartino. “To some extent it seems todrive them into inflamed areas.”

The stem cells then got to workrepairing the damage caused by thedisease. Brain sections showed thataxons in close contact with the cellsbegan to develop loosely compactedmyelin sheets, a clear sign that theywere remyelinating. “Some of thesecells caused direct remyelination andsome inhibited astrogliosis, thusallowing resident oligodendrocytes tobegin remyelination as well”, explainsMartino. Some of the injected cellsdifferentiated into neurons. Reductionof astrocytic scarring and productionof growth factors that encourageneurorestoration were also seen.

Even more remarkable was therecovery of the mice, which began asearly as 5 days after intravenous

Neural stem cells remyelinate neurons in MS model