UCI mouse study points to new treatments to limit effects of neurological disorder.
Using a drug compound created to treat cancer, University of California, Irvine neurobiologists have disarmed the brain’s response to the distinctive beta-amyloid plaques that are the hallmark of Alzheimer’s disease.
Kim Green and colleagues with UCI’s Institute for Memory Impairments and Neurological Disorders found that flushing away the abundant inflammatory cells produced in reaction to beta-amyloid plaques restored memory function in test mice. Their study showed that these cells, called microglia, contribute to the neuronal and memory deficits seen in this neurodegenerative disease. Results appear in the journal Brain.
“Our findings demonstrate the critical role that inflammation plays in Alzheimer’s-related memory and cognitive losses,” said Green, an assistant professor of neurobiology & behavior. “While we were successful in removing the elevated microglia resulting from beta-amyloid, further research is required to better understand the link among beta-amyloid, inflammation and neurodegeneration in Alzheimer’s.”
The neurobiologists treated Alzheimer’s disease model mice with a small-molecule inhibitor compound called pexidartinib, or PLX3397, which is currently being used in several phase 2 oncology studies and a phase 3 clinical trial to treat a benign neoplasm of the joints.
The inhibitor works by selectively blocking signaling of microglial surface receptors, known as colony-stimulating factor 1 receptors, which are necessary for microglial survival and proliferation in response to various stimuli, including beta-amyloid. This led to a dramatic reduction of these inflammatory cells, allowing for analysis of their role in Alzheimer’s. The researchers noted a lack of neuron death and improved memory and cognition in the pexidartinib-treated mice, along with renewed growth of dendritic spines that enable brain neurons to communicate.
Green said that although the compound swept away microglia, the beta-amyloid remained, raising new questions about the part these plaques play in Alzheimer’s neurodegenerative process.
In healthy tissue, microglia act as the first and main form of immune defense in the central nervous system. But in a disease state, such as Alzheimer’s, microglia appear to turn against the healthy tissue they were originally assigned to protect, causing inflammation in the brain. The beta-amyloid plaques in brain areas related to Alzheimer’s disease are rich with these rogue microglia, Green added.
“Our work is telling us that these cells may contribute to the disease process, and targeting them with such specific drugs is a promising new approach,” he said.
Elizabeth Spangenberg, Rafael Lee, Allison Najafi, Rachel Rice, Monica Elmore and Mathew Blurton-Jones of UCI and Brian West of Plexxikon Inc. contributed to the study.
Funding: The study was supported by the National Institutes of Health (grants 1R01NS0833801 and P50AG016573), the Whitehall Foundation, the American Federation for Aging Research and the Alzheimer’s Association. Plexxikon Inc. provided the pexidartinib compounds.
Source: UC Irvine
Image Credit: Image is credited to Green lab / UCI.
Original Research: Abstract for “Eliminating microglia in Alzheimer’s mice prevents neuronal loss without modulating amyloid-β pathology” by Elizabeth E. Spangenberg, Rafael J. Lee, Allison R. Najafi, Rachel A. Rice, Monica R. P. Elmore, Mathew Blurton-Jones, Brian L. West, and Kim N. Green in Brain. Published online February 26 2016 doi:10.1093/brain/aww016
Abstract
Eliminating microglia in Alzheimer’s mice prevents neuronal loss without modulating amyloid-β pathology
In addition to amyloid-β plaque and tau neurofibrillary tangle deposition, neuroinflammation is considered a key feature of Alzheimer’s disease pathology. Inflammation in Alzheimer’s disease is characterized by the presence of reactive astrocytes and activated microglia surrounding amyloid plaques, implicating their role in disease pathogenesis. Microglia in the healthy adult mouse depend on colony-stimulating factor 1 receptor (CSF1R) signalling for survival, and pharmacological inhibition of this receptor results in rapid elimination of nearly all of the microglia in the central nervous system. In this study, we set out to determine if chronically activated microglia in the Alzheimer’s disease brain are also dependent on CSF1R signalling, and if so, how these cells contribute to disease pathogenesis. Ten-month-old 5xfAD mice were treated with a selective CSF1R inhibitor for 1 month, resulting in the elimination of ∼80% of microglia. Chronic microglial elimination does not alter amyloid-β levels or plaque load; however, it does rescue dendritic spine loss and prevent neuronal loss in 5xfAD mice, as well as reduce overall neuroinflammation. Importantly, behavioural testing revealed improvements in contextual memory. Collectively, these results demonstrate that microglia contribute to neuronal loss, as well as memory impairments in 5xfAD mice, but do not mediate or protect from amyloid pathology.
“Eliminating microglia in Alzheimer’s mice prevents neuronal loss without modulating amyloid-β pathology” by Elizabeth E. Spangenberg, Rafael J. Lee, Allison R. Najafi, Rachel A. Rice, Monica R. P. Elmore, Mathew Blurton-Jones, Brian L. West, and Kim N. Green in Brain. Published online February 26 2016 doi:10.1093/brain/aww016
