Year: 2010
Type: article
Abstract: 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 in senile plaques. Microglia, the primary immune effector cells in the brain, continually monitor the tissue parenchyma for pathological alterations and become activated in AD. 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, 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). To examine the role of CX3CL1-CX3CR1 signaling in Alzheimer's disease, we examined the effects of CX3CR1 deficiency on both beta-amyloid and MAPT pathologies in the APPPS1 (and R1.40) and hTau mouse models of AD, respectively. CX3CR1 deficiency resulted in a gene dose-dependent reduction in beta-amyloid deposition in both the APPPS1 and R1.40 transgenic mouse models of AD that was associated with altered microglial activation, reduced numbers of plaque associated microglia and yet enhanced removal of beta-amyloid. By contrast, CX3CR1 deficiency in the hTau mouse model of MAPT pathology resulted in enhanced microglial activation, phosphorylation and aggregation of MAPT and behavioral impairments. Additional in vitro experiments demonstrate that microglial activation and CX3CR1 deficiency elevates the level of active p38 MAPK and enhances MAPT hyperphosphorylation within neurons that can be blocked by administration of a specific p38 MAPK inhibitor. Our results suggest that CX3CR1 deficiency has opposing effects on the development of the two primary pathologies observed in AD and suggests that “anti-inflammatory” therapies may have opposite effects on AD pathologies at different stages of disease progression.
Source: Alzheimer s & Dementia
Language: English
Subfield: Neurology
Field: Neuroscience
Domain: Life Sciences
Open Access status: bronze
OpenAlex ID: W2025438987