New blood cells help an overburdened brain

Abstract

Neurodegenerative disorders are all too common and devastating for those affected and their family and friends. Studies of patients and animal models not only provides information necessary for developing preventative and therapeutic approaches, but can also reveal novel basic principles of neuroscience. Such is the case with studies of glycolipid storage disorders that result in progressive neuronal dysfunction and degeneration. These disorders, which include Tay–Sachs, Sandhoff and Gaucher's diseases, are caused by genetic defects in lysosomal enzymes that are necessary for the degradation of glycosphingolipids, thus resulting in excessive accumulation of glycolipids in lysosomes. In the nervous system of these patients, the intracellular accumulation of glycolipids can trigger damage and death of neurons and oligodendrocytes. Because the glycolipids accumulate in the cells that degenerate, it had been assumed that the cells ‘self-destruct’. Surprisingly, Wada and co-workers 1xMicroglial activation precedes acute neurodegeneration in Sandhoff disease and is suppressed by bone marrow transplantation. Wada, R. et al. Proc. Natl. Acad. Sci. U.S.A. 2000; 97: 10954–10959Crossref | PubMedSee all References1 now provide compelling evidence that neurons that accumulate the ganglioside GM2 in Sandhoff disease do not commit suicide, but instead are killed by enraged microglia.Wada and co-workers now provide compelling evidence that neurons that accumulate the ganglioside GM2 in Sandhoff disease do not commit suicide...Using a mouse model in which disruption of the β-hexosaminidase gene causes a neurological phenotype similar to Sandhoff disease in humans, Wada et al. show, using cDNA microarray analysis, that inflammation-like changes in gene expression occur in the brains of the Sandhoff mice. They further show that activated microglia are present in vulnerable brain regions before evidence of neuronal death. Remarkably, when bone marrow from normal mice was transplanted into Sandhoff mice depleted of bone marrow cells by treatment with γ-radiation, the activation of microglia and neuronal death were suppressed. However, the amelioration of neuronal damage was not associated with a decrease in ganglioside accumulation in the neurons, suggesting that it is not the lack of degradation of glycolipid that is responsible for the demise of neurons in Sandhoff disease. For more than 15 years it had been known that bone marrow transplantation can halt the progression of the disease symptoms outside of the nervous system in animals with lysosomal storage disorders 2xCorrection of feline arylsulphatase B deficiency (mucopolysaccharidosis VI) by bone marrow transplantation. Gasper, P.W. et al. Nature. 1984; 312: 467–469Crossref | PubMed | Scopus (61)See all References2 as a result of repopulation of organs, such as the spleen and liver, with macrophages. However, it was not known if, and how, the neurodegenerative process might be affected by bone marrow transplantation. The work of Wada et al. strongly suggests that β-hexosaminidase deficiency in microglia causes them to become hyper-reactive and attack neurons in the brainstem and spinal cord. Replacing the enraged microglia with less-reactive macrophages from normal mice results in a suppression of the inflammatory cascade that probably kills the neurons in Sandhoff patients.These new findings also reveal an important link between blood cells, brain function and disease. Whereas the involvement of inflammatory processes, in which microglia play a central role, is now well-established in neurodegenerative disorders, it had been assumed that the microglia were resident cells rather than blood-derived macrophages. However, the microglial population can turnover much more rapidly than previously appreciated, particularly in the settings of injury and disease. This raises the intriguing possibility that other subpopulations of bone marrow cells, some of which might be capable of differentiating into neurons and oligodendrocytes, might circulate and enter the brain. Findings from recent studies have shown that stem cells in the brain are responsive to environmental stimuli, ranging from mental and physical exercise to dietary restriction 3xDietary restriction increases survival of newly-generated neural cells and induces BDNF expression in the dentate gyrus of rats. Lee et al. J. Mol. Neurosci. 2000; 15: 105–113See all References3. Clearly, it will be of considerable interest to determine the effects of such stimuli on blood cells that take up residency in the brain and to see whether such alterations in blood–brain cell transfer play a role in neurodegenerative conditions other than lysosomal storage disorders.