One problem in the Bahn et al. paper is that it lacks confirmation that these changes occur with real Down's syndrome cells, like primary neurons or astrocytes in culture, or in the Down's brain. When they looked at the expression of the AβPP gene, they found that that was also reduced in their Down's syndrome cells, which nobody has seen. There may be some artifact of the cell isolation that has led to amplification of a particular cell type into neurospheres.

View all comments by Bruce Yankner

This study shows very similar results to what we reported at the last Neuroscience meeting in San Diego. We found that secreted-type AβPP dose-dependently increased glial differentiation of normal human neural stem cells, and that transfection of the wildtype AβPP gene almost eliminated neuronal differentiation. Bahn et al. found extremely high levels of glial differentiation in the neural stem cells isolated from Down's syndrome patients, which may have an overdose of AβPP because of chromosome 21 trisomy. However, these authors found that AβPP expression was slightly decreased in the neurospheroid (undifferentiated neural stem cells). They also found reduced expression of REST, and REST regulated genes that highly relate to neuronal plasticity.

This finding may contribute to the reduction of neurite length and abnormal morphology of neurally differentiated stem cells. Since Down’s patients have high AβPP expression, and REST does not directly regulate AβPP expression, both mechanisms of glial differentiation and suppression of AβPP gene expression in the Down's syndrome...  Read more

This study shows very similar results to what we reported at the last Neuroscience meeting in San Diego. We found that secreted-type AβPP dose-dependently increased glial differentiation of normal human neural stem cells, and that transfection of the wildtype AβPP gene almost eliminated neuronal differentiation. Bahn et al. found extremely high levels of glial differentiation in the neural stem cells isolated from Down's syndrome patients, which may have an overdose of AβPP because of chromosome 21 trisomy. However, these authors found that AβPP expression was slightly decreased in the neurospheroid (undifferentiated neural stem cells). They also found reduced expression of REST, and REST regulated genes that highly relate to neuronal plasticity.

This finding may contribute to the reduction of neurite length and abnormal morphology of neurally differentiated stem cells. Since Down’s patients have high AβPP expression, and REST does not directly regulate AβPP expression, both mechanisms of glial differentiation and suppression of AβPP gene expression in the Down's syndrome patient’s stem cells may need more investigation. If AβPP promotes glial differentiation of neural stem cells, it may explain in part why Down's syndrome patients develop AD-like pathology by age 30-40 years.

View all comments by Kiminobu Sugaya

The recent study demonstrating that tauroursodeoxycholic acid exerts significant therapeutic effects in a transgenic mouse model of Huntington's Disease (HD) is extremely intriguing. This agent was previously demonstrated to stabilize mitochondria and inhibit release of cytochrome-c, which has been linked to apoptotic cell death. This prevents activation of downstream caspases. It is possible that similar mechanisms may play a role in Alzheimer's Disease (AD) pathogenesis. There is substantial evidence showing that a number of markers for apoptotic cell death are increased in AD postmortem brain tissue. There is also substantial evidence for mitochondrial dysfunction in AD. Decreases in cytochrome oxidase activity have been demonstrated both in postmortem as well as in peripheral tissues such as platelets. Reductions in alpha-ketoglutorate dehydrogenase activity are found in both fibroblasts as well as in brain tissue.

There is also a large body of evidence implicating increased oxidative damage in AD. All of these processes may be linked to mitochondrial dysfunction....  Read more

The recent study demonstrating that tauroursodeoxycholic acid exerts significant therapeutic effects in a transgenic mouse model of Huntington's Disease (HD) is extremely intriguing. This agent was previously demonstrated to stabilize mitochondria and inhibit release of cytochrome-c, which has been linked to apoptotic cell death. This prevents activation of downstream caspases. It is possible that similar mechanisms may play a role in Alzheimer's Disease (AD) pathogenesis. There is substantial evidence showing that a number of markers for apoptotic cell death are increased in AD postmortem brain tissue. There is also substantial evidence for mitochondrial dysfunction in AD. Decreases in cytochrome oxidase activity have been demonstrated both in postmortem as well as in peripheral tissues such as platelets. Reductions in alpha-ketoglutorate dehydrogenase activity are found in both fibroblasts as well as in brain tissue.

There is also a large body of evidence implicating increased oxidative damage in AD. All of these processes may be linked to mitochondrial dysfunction. Furthermore, mitochondrial dysfunction is linked to beta-amyloid production as recently demonstrated by Busciglio et al. Agents that can stabilize mitochondria and prevent their involvement in apoptotic cell death pathways may therefore be useful in treating a number of neurodegenerative diseases including AD.

View all comments by M. Flint Beal