Alzheimer's disease (AD), the most common cause of dementia in the elderly, is now the seventh major cause of death in the United States. AD is characterized and diagnosed by distinctive neuropathological alterations including extracellular deposits of the ?-amyloid (A?) peptide, intracellular aggregates of the microtubule associated protein tau (MAPT) in neurons and marked neuroinflammation. Similarly in non-AD tauopathies, there is both abundant MAPT pathology and neuroinflammation. However, the exact mechanistic relationship between neuroinflammation and the various brain pathologies remains unclear. Recent studies have implicated neuronal-microglial signaling through the fractalkine receptor (CX3CR1) in neuroprotection and neurodegeneration. To examine the role of CX3CL1-CX3CR1 signaling in Alzheimer's disease and non- AD tauopathies, we conducted preliminary studies to examine the effects of CX3CR1 deficiency on both A? and MAPT pathologies. Notably, CX3CR1 deficiency resulted in a reduction in A? pathologies in two different mouse models of AD that was associated with altered microglial activation, while conversely, CX3CR1 deficiency in the hTau mouse model of MAPT pathology resulted in enhanced microglial activation, phosphorylation and aggregation of MAPT and behavioral impairments. Additional studies in both the A? and MAPT models suggests that IL1 signaling may contribute to the CX3CR1 dependent alterations in AD brain pathologies. The hypothesis to be examined in the current studies is that soluble CX3CL1 released from neurons signals to CX3CR1 within microglia and plays a unique role in AD phenotypes via blocking phagocytic removal of A? by microglia and reducing phosphorylation and aggregation of MAPT within neurons via mechanisms that involve IL1. These studies will utilize state-of-the art mouse models of A? and MAPT pathologies, as well as CXC3CR1 knockout mice and CX3CL1 knockouts and transgenic mice to examine the effects of biochemistry, gene expression, neuropathology and behavior.
The Specific Aims of this proposal are to: 1. Determine the Role of CX3CL1-CX3CR1 Signaling in a Mouse Model of A? Deposition. 2. Determine the Role of CX3CL1-CX3CR1 Signaling in a Mouse Model of MAPT Pathology. 3. Determine the Role of IL1 Signaling in CX3CR1 Dependent Alterations in AD Pathologies.
Numerous studies have demonstrated that altered neuroinflammation, including microglial activation is an invariant feature observed in AD and non-AD tauopathies. However, it remains unclear how altered microglial activation and signaling between neurons and microglia contributes to the primary pathological hallmarks of AD and non-AD tauopathies and at different stages of disease progression. The current studies seek to examine whether alterations in fractalkine signaling contributes uniquely to the development of A2 and MAPT pathologies, information that will be critical in the development of therapies aimed at blocking disease pathologies at different stages of disease progression.
|Maphis, Nicole M; Jiang, Shanya; Binder, Jessica et al. (2017) Whole Genome Expression Analysis in a Mouse Model of Tauopathy Identifies MECP2 as a Possible Regulator of Tau Pathology. Front Mol Neurosci 10:69|
|Maphis, Nicole; Jiang, Shanya; Xu, Guixiang et al. (2016) Selective suppression of the ? isoform of p38 MAPK rescues late-stage tau pathology. Alzheimers Res Ther 8:54|
|Andreasson, Katrin I; Bachstetter, Adam D; Colonna, Marco et al. (2016) Targeting innate immunity for neurodegenerative disorders of the central nervous system. J Neurochem 138:653-93|
|Maphis, Nicole; Xu, Guixiang; Kokiko-Cochran, Olga N et al. (2015) Loss of tau rescues inflammation-mediated neurodegeneration. Front Neurosci 9:196|
|Maphis, Nicole; Xu, Guixiang; Kokiko-Cochran, Olga N et al. (2015) Reactive microglia drive tau pathology and contribute to the spreading of pathological tau in the brain. Brain 138:1738-55|
|Komuro, Yutaro; Xu, Guixiang; Bhaskar, Kiran et al. (2015) Human tau expression reduces adult neurogenesis in a mouse model of tauopathy. Neurobiol Aging 36:2034-42|
|Katsumoto, Atsuko; Lu, Haiyan; Miranda, Aline S et al. (2014) Ontogeny and functions of central nervous system macrophages. J Immunol 193:2615-21|
|Lee, Sungho; Xu, Guixiang; Jay, Taylor R et al. (2014) Opposing effects of membrane-anchored CX3CL1 on amyloid and tau pathologies via the p38 MAPK pathway. J Neurosci 34:12538-46|
|Bhaskar, Kiran; Maphis, Nicole; Xu, Guixiang et al. (2014) Microglial derived tumor necrosis factor-? drives Alzheimer's disease-related neuronal cell cycle events. Neurobiol Dis 62:273-85|
|Cameron, Brent; Tse, Wayne; Lamb, Raza et al. (2012) Loss of interleukin receptor-associated kinase 4 signaling suppresses amyloid pathology and alters microglial phenotype in a mouse model of Alzheimer's disease. J Neurosci 32:15112-23|