1. The roles of fractalkine signaling in neurodegenerative disease
- Author
-
Bruce T. Lamb
- Subjects
Genetically modified mouse ,Microglia ,business.industry ,Neurodegeneration ,Clinical Neurology ,lcsh:Geriatrics ,medicine.disease ,Neuroprotection ,lcsh:RC346-429 ,lcsh:RC952-954.6 ,Cellular and Molecular Neuroscience ,medicine.anatomical_structure ,Knockout mouse ,CX3CR1 ,medicine ,Neurology (clinical) ,Senile plaques ,business ,Neuroscience ,Molecular Biology ,Neuroinflammation ,lcsh:Neurology. Diseases of the nervous system ,Lecture Presentation - Abstract
Background The primary neuropathological characteristics of AD include intracellular, filamentous inclusions of hyperphosphorylated microtubule associated protein tau (MAPT) in neurons (neurofibrillary tangles, NFTs) and extracellular deposits of the beta-amyloid peptide (A-Beta) in senile plaques. While A-Beta plaques are unique to AD, NFTs are observed in a wide variety of neurodegenerative diseases, including AD, frontotemporal dementia, cortical basal degeneration and other disorders, collectively termed tauopathies. Microglia, the primary immune effector cells in the brain, continually monitor the tissue parenchyma for pathological alterations and become activated in AD and other tauopathies. Increasing evidence suggests that microglia contribute to the pathopysiology of AD including; correlational studies in human AD and mouse models, retrospective epidemiological studies demonstrating that use of nonsteroidal anti-inflammatory drugs (NSAIDs) substantially reduces AD risk, genome-wide association studies of human AD and studies utilizing genetically modified mouse models. Neuronal-microglial communication through the chemokine fractalkine (CX3CL1) and its cognate receptor, CX3CR1, plays a critical role in neuroinflammation and neuroprotection. First, CX3CL1 is highly expressed by neurons while CX3CR1 is only expressed by microglia within the CNS. Second, CX3CL1 is neuroprotective in models of neuroinflammation. Finally, studies of Cx3cr1 knockout mice revealed enhanced neurodegeneration in mouse models of amyotrophic lateral sclerosis (ALS) and Parkinson’s Disease (PD).
- Published
- 2012