Lewy bodies are aggregations of misfolded proteins in nerve cells that can kill them off and cause dementia. When Lewy bodies form in neurons, they can cause “dementia with Lewy bodies” or DLB. After Alzheimer’s disease, DLB is the second-most common type of age-related dementia, and it afflicted the beloved comedian Robin Williams, who took his own life earlier this year.
Scientists at the Sue and Bill Gross Stem Cell Research Center and the Institute for Memory Impairments and Neurological Disorders at UC Irvine have examined the ability of transplanted neural stem cells to ameliorate the symptoms of DLB is an animal model system.
Particular strains of laboratory mice have been genetically engineered to form Lewy bodies in their brains and show some of the symptoms of DLB. Natalie Goldberg and her colleagues used neural stem cells to treat some of these mice in order to determine if these cells could decrease the pathological consequences of DLB.
Transplantation of neural stem cells into the brains of these DLB mice resulted in increases in cognitive and motor function. A battery of tests established this. For example, the Rotarod test places the mouse on a rod that is then rotated at a specific speed. Normal mice can move around the rod and keep from falling off, but mice with motor or balance problems will fall off the rod prematurely. Cognitive tests included Novel Object Recognition (NOR) and Novel Place Recognition (NPR) tests, which are low-stress tasks that quantify the proportion of time spent examining a novel object and provide data on memory. In these tests, the mice that received the neural stem cell transplantation did significantly better than their non-treated siblings.
Goldberg and his team then asked how these cells improved the cognitive and motor function of the DLB mice. It turns out that neutral stem cells secrete respectable amounts of brain-derived neurotrophic factor (BDNF). Goldberg suspected that this growth factor was a major contributor to the healing capabilities of neural stem cells. Therefore, Goldberg’s team engineered neural stem cells that could not make BDNF and injected those directly into the brains of DLB mice. These mutant neural stem cells were incapable of improving the cognitive or motor function of these mice.
To further test her hypothesis, Goldberg then engineered a virus that would infect neurons and overexpress BDNF and used that to treat her DLB mice. Interestingly, the BDNF-expressing virus did a pretty good job at restoring motor functions in these DLB mice, but did not restore the cognitive functions.
Thus, while the secretion of BDNF by neural stem cells is important for their restorative capacities, but it is only part of the means they use to heal affected brains. Goldberg and her coworkers showed that the transplanted neural stem cells did not improve the pathology of the brains, they did preserve neural pathways that use the neurotransmitters dopamine and glutamate.
The neural stem cells used in these experiments were mouse neural stem cells. Before work like this can advance to human clinical trials, human neural stem cells must be tested. Since other neurodegenerative diseases like Parkinson’s disease also result from Lewy body formation in specific cells, neural stem cell treatments might prove beneficial for patients with much diseases.
This work was published in Stem Cell Reports October 2015 DOI: 10.1016/j.stemcr.2015.09.008.