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Sungho Lee
Mouse Model of Alzheimer's Disease Deficient for Fractalkine Receptor Exhibits Reduced Beta-Amyloid Deposition
Sungho Lee, Nicholas H. Varvel and Bruce T. Lamb
Department of Neurosciences, Department of Genetics
Cleveland Clinic, Case Western Reserve University School of Medicine
Alzheimer’s disease (AD) is the leading cause of dementia in the elderly. It is characterized by distinct neuropathological
hallmarks including extracellular deposits of beta-amyloid peptide, which is proteolytically cleaved from the amyloid
precursor protein (APP). In addition, there is considerable evidence for altered inflammation within the AD brain, including
increased numbers of inflammatory cells and expression of a variety of pro-inflammatory molecules. Microglia, the primary
immune effector cells in the brain, continually monitor the brain for pathological alterations and become activated in most
neurodegenerative conditions including AD. Depending upon local conditions within the brain, it has been postulated that
microglia can either play a neuroprotective role such as the removal of debris, or may be directly involved in the
pathogenesis of neurodegenerative diseases through the production of neurotoxic cytokines. Recent studies indicate that
microglia may play a direct pathogenic role in neurodegeneration via alteration in communication with neurons mediated
by the microglial fractalkine receptor, CX3CR1. Cx3cr1 deficient mice exhibit increased neurotoxicity and worsening of
phenotypes in a variety of mouse models of neurodegenerative disease. To gain further insight into the role of
inflammation in AD pathogenesis, we performed genetic crosses between the APPPS1 mouse model of AD and Cx3cr1
deficient mice. As expected, transgene-derived APP and APP processing products are largely unaltered. Interestingly,
transgenic mice both heterozygously and homozygously deficient for Cx3cr1 exhibit gene dosage-dependent reduction in
beta-amyloid deposition when compared to control APPPS1 animals. Furthermore, these animals demonstrate reduced
microglial activation, as indicated by the decreased number of microglia surrounding each beta-amyloid deposit. These data
suggest that fractalkine signaling between microglia and neurons mediate pivotal roles in AD pathogenesis, most likely with
regards to beta-amyloid clearance.
Supported by American Federation for Aging Research
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