For personal use. Only reproduce with permission from The Lancet Publishing Group.

Adult bone marrow cells areremarkably versatile; they possess theability to differentiate into muscle,skin, liver, and lung cells, to name buta few. Now, for the first time, Eva Mezey (National Institute ofNeurological Disorders and Stroke,MA, USA) has shown that bonemarrow cells can enter the brain andproduce various neural cells; the firsttime this has been shown in humans.

Previously, several groups haveshown that, in mice, bone marrowcells are able to enter the brain andadopt a neuronal phenotype. Mezeystudied the brains of four femalepatients who had received bonemarrow transplants from male donors(Proc Natl Acad Sci 2003; publishedonline January 21, DOI 10.1073/pnas.0336479100) The transplants hadbeen given to treat leukaemia andother non-neurological disorders, and the patients varied in age and post-transplant survival time.

Y-chromosome positive cells werefound in the brains of all patients.Most cells were non-neuronal, but a few in the neocortex andhippocampus, expressed neuronalmarkers. “This study shows that somekind of cell in bone marrow, mostlikely a stem cell, has the capacity toenter the brain and form neurons”,said Mezey.

Mezey reports that the donor-derived cells found in the brains werein mixed clusters, rather than singlecells dotted about randomly, hypo-thesising that single cells migrated intoan “area of need” where they thendivided and differentiated.

Malcolm Allison (Imperial College,London, UK) is cautious, however.“What they have shown is a scatteringof engrafted cells that have apparentlydifferentiated. The rates of trans-differentiation are quite low, estimatedat one Y-positive neuron in 2000–4000indigenous neurons. If this is going to

translate into a therapy, one will need tobe able to get the engrafted cells toundergo a robust clonal expansion intheir new environment.”

Indeed, there is still much work tobe done. “We need to determine howcells in the blood enter the brain, howto induce them to enter in largernumbers, how to promote theirdifferentiation into neurons, and howto target them to areas of need”, saidMezey. “To be frank, we have hadtrouble convincing some members ofthe scientific community that thiscould happen. As I see it, acceptingthis idea is the first step towardsaccepting the suggestions that adultstem cells could some day be used to replace neural elements lost toneurodegenerative diseases, stroke, ortrauma. These studies are very muchthe beginning, but scientists shouldstart to look down this road and findout if and how we can go further.”Helen Pilcher

Human bone marrow makes neurons

THE LANCET Neurology Vol 2 March 2003 http://neurology.thelancet.com138

Blood A� binding agents reduce build-up in the brain

Newsdesk

Researchers in the US have found thatmolecules that bind amyloid-�peptide (A�) in the blood can reducecerebral build-up of the protein andcut down the formation of amyloidplaques in mice (J Neurosci 2003; 23:29–33). This finding could open theway for the design of new drugs toprevent Alzheimer’s disease (AD).

The build-up of A� plaques in the brain is a hallmark of AD, andperiphery–brain A� dynamics may beessential in this process. “Animalstudies have shown cerebral A� loadcan be reduced by A� antibodies—perhaps by shipping A� out of thebrain or by stopping it going in—buttests on vaccines have been stoppedbecause of adverse effects”, says KarenDuff (Centre for Dementia Research,Nathan Kline Institute, New YorkUniversity, USA). “We wonderedwhether brain A� levels could bealtered by binding A� peripherallyusing a non-immunological method.”

The researchers bred micegenetically predisposed to developing

cerebral A� plaques, and injectedthem intraperitoneally with eithergelsolin or the ganglioside GM1, bothknown for their A� binding affinity.Tests showed that animals treatedwith either compound for 3 weekshad around 50% less extractablecerebral A� than controls. Further,immunohistochemical assays revealedthey also had around 50% less brain surface (cerebral cortex andhippocampus) affected by A�plaques. Diffuse A� was particularlyreduced, which suggests thatit is theinitial target of drug action. A�concentrations in the blood werechanged in GM1-treated mice,suggesting that this drug (and perhaps both) works by affecting theperiphery–brain dynamics. Intra-cerebroventricular injections of GM1left concentrations of A� in the CNSunchanged, further supporting theidea.

GM1 was, however, unable toshift A� from brains with heavyamyloid burdens, probably because

old plaques become too stable. Anytherapy based on these compounds is,therefore, more likely to be effectivein the preventive setting. But theresearchers do not actually advocatethe use of these particular agents forthe treatment of AD. “Rather, we seethis as an initial step in thedevelopment of compounds that actin this manner, and as proof-of-concept for a prophylactic approachthat may be more flexible, morereliable, and less likely to cause side-effects in long-term administrationparadigms than immunisation-basedtherapies”, says Duff’s coauthorYasuji Matsuoka.

Francisco Wandosell (Centro deBiologia Molecular Severo Ochoa,Universidad Autónoma, Madrid,Spain) commented, “such an app-roach would be very relevant in AD,but potential immunological hitchesshould be taken into account toensure we avoid the mistakes madewith A� vaccination”.Adrian Burton