Stimulating the growth of new neurons to replace those lost in Alzheimer’s disease is an intriguing therapeutic possibility, but it’s unknown whether the factors that cause Alzheimer’s disease will allow the new neurons to thrive and function normally.
Although it had long been assumed that neurons cannot be renewed, it is now well established that new neurons are generated throughout the lives of mammals. One brain region in which new neurons are born in adults, the hippocampus, is involved in learning and memory and affected severely by Alzheimer’s disease.
The researchers studied the development of neurons born in the hippocampus of adult mice genetically engineered to produce high levels of human A? in the brain. Surprisingly, A? initially accelerated the development of newborn neurons but then profoundly impaired their maturation at later stages of development.
“Interestingly,” said study author Dr. Li Gan, “we were able to protect the newborn neurons and ensure their normal development with drugs that counteract A?-induced abnormalities in neural network activity. It is possible that these drugs could support the development of neurons from stem cells even in the hostile environment of the Alzheimer’s disease brain.”
In a complementary study, researchers focused on apoE4, the major genetic risk factor for Alzheimer’s disease. The team used genetically engineered mice to study the effects of different human apoE variants on the maturation of neural stem cells or progenitor cells, from which new neurons develop in the adult brain. They found that apoE4 also impairs the development of new neurons in the hippocampus and identified drug treatments that could block these detrimental effects.
“Our findings suggest that apoE4 inhibits the development of newborn neurons by impairing specific signaling pathways and that boosting these pathways with drugs may be of therapeutic benefit,” said Dr. Huang. “It might allow us to encourage the development of new neurons from stem cells to replace those lost in apoE4 carriers with Alzheimer’s disease.”
“Although stem cell therapy for Alzheimer’s disease is still a long ways off, these studies have identified strategies to overcome major obstacles in the path towards this goal,” said Lennart Mucke, coauthor of one of the studies. “They clearly demonstrate that drugs can be used to improve the development of newborn neurons in memory centers of the adult brain, even in the presence of toxic factors widely presumed to cause Alzheimer’s disease.”
References:
1. Li Gan, et al. Imbalance between GABAergic and Glutamatergic Transmission Impairs Adult Neurogenesis in an Animal Model of Alzheimer’s Disease. Cell Stem Cell, Volume 5, Issue 6, 624-633, 4 December 2009.
2. Yadong Huang, et al. GABAergic Interneuron Dysfunction Impairs Hippocampal Neurogenesis in Adult Apolipoprotein E4 Knockin Mice. Cell Stem Cell, Volume 5, Issue 6, 634-645, 4 December 2009
