Journal
JOURNAL OF NEUROSCIENCE
Volume 34, Issue 37, Pages 12538-12546Publisher
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.0853-14.2014
Keywords
Alzheimer's disease; CX3CL1; microglia; phagocytosis
Categories
Funding
- Alzheimer's Association Multi-Center Program
- National Institute on Aging [AG023012]
- National Institute of Neurological Disorders nd Stroke [NS047804]
- National Multiple Sclerosis Society Research [4550]
- National Research Service Award Fellowship [F30 NS068003]
- National Research Service Award [T32 GM007250, NS067431]
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Several Alzheimer's disease (AD) risk genes are specifically expressed by microglia within the CNS. However, the mechanisms by which microglia regulate the pathological hallmarks of AD-extracellular deposition of beta-amyloid (A beta) and intraneuronal hyperphosphorylation of microtubule-associated protein tau (MAPT)-remain to be established. Notably, deficiency for the microglial CX3CR1 receptor has opposing effects on A beta and MAPT pathologies. CX3CL1, the neuronally derived cognate ligand for CX3CR1, signals both in membrane-anchored and soluble forms. In this study, we sought to determine the relative contribution on membrane-anchored versus soluble CX3CL1 in regulating the microglia-mediated amelioration of A beta pathology, as well as provide insight into the potential downstream microglial-based mechanisms. As expected, CX3CL1 deficiency reduced A beta deposition in APPPS1 animals in a similar manner to CX3CR1 deficiency. Surprisingly, however, CX3CL1-deficient APPPS1 animals exhibited enhanced neuronal MAPT phosphorylation despite reduced amyloid burden. Importantly, neither of these phenotypes was altered by transgenic expression of the soluble CX3CL1 isoform, suggesting that it is the membrane-anchored version of CX3CL1 that regulates microglial phagocytosis of A beta and neuronal MAPT phosphorylation. Analysis of transcript levels in purified microglia isolated from APPPS1 mice with the various CX3CL1/CX3CR1 genotypes revealed increased expression of inflammatory cytokines and phagocytic markers, which was associated with activation of p38 mitogen-activated protein kinase and A beta internalization within microglia. Together, these studies challenge the frustrated phagocytosis concept and suggest that neuronal-microglial communication link the two central AD pathologies.
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