The prominent filamentous inclusions of microtubule-associated protein tau (MAPT) and neurodegeneration are hallmarks of many neurodegenerative tauopathies. Although, the exact etiology of many of these tauopathies remains elusive, neuropathologically, they are characterized by intracellular aggregates of hyperphosphorylated MAPT, neuroinflammation and cell death. Increasing evidence suggests that neuroinflammation may directly contribute to the pathophysiology of neurodegenerative tauopathies. However, these studies are largely correlative, and do not provide direct evidence of the role of neuroinflammation in the neurodegenerative disease process. We have recently provided compelling evidence that neuroinflammation, cell-autonomous to microglia, accelerates MAPT phosphorylation, aggregation and behavioral impairment in a mouse model of tauopathy (hTau). Notably, the effects of microglial activation on MAPT pathology were enhanced when mice were deficient for the microglial-specific fractalkine receptor, CX3CR1. We also demonstrated that interleukin-1 (IL-1) released by reactive microglia induces MAPT phosphorylation in primary neurons via activating neuronal IL1-receptor (IL1-R) and p38 mitogen activated protein kinase (p38 MAPK) pathway. Taken together, these results suggest that inhibition of neuronal IL1- R/p38 MAPK may represent a unique potential drug target for human tauopathies. Numerous studies have established that Myeloid Differentiation primary response gene 88 (MyD88) is a key downstream adapter protein for IL-1Rs as well as upstream for p38 MAPK activation. Recent studies have suggested that genetic deficiency of MyD88 is protective against hypoxia induced brain injury and mouse model of systemic inflammation. However, the role of MyD88 in mediating IL-1 induced MAPT pathology is unclear. Given the importance of IL-1 and IL1-R within the immune cells of the brain in regulating innate and adoptive immunity, the goal of the current proposal is to specifically target neuronal-MyD88 and study its effect on p38 MAPK activation, MAPT pathology, neuroinflammation, neurodegeneration and cognitive function in mouse models of systemic inflammation (lipopolysaccharide/LPS) and tauopathy (hTau). This will be studied under two specific aims: 1) Study the effect of neuron-restricted deletion of MyD88 on LPS induced MAPT pathology, neuroinflammation, neurodegeneration and behavioral function in MyD88fl/fl/CamKII-Cre transgenic mice. 2) Generate hTau mice deficient for neuronal MyD88 via crossing hTau, hTau-Cx3cr1-/- mice to MyD88fl/fl/CamKII- Cre transgenic mice, and study MAPT pathology, neuroinflammation, neurodegeneration and behavioral function at different ages. These studies will provide greater understanding of the neuron-specific IL1-R/MyD88 signaling in tauopathies and determine whether MyD88 can serve as a potential therapeutic target against inflammation-mediated MAPT pathology in human tauopathies.
Accumulating evidence suggests that the age-related brain inflammation may play an important role in tau-mediated neurodegeneration in numerous human tauopathies. A recent study from our group has provided compelling evidence that microglia-specific neuroinflammation accelerates tau pathology and cognitive impairment in humanized mouse model of tauopathy (hTau). Notably, interneukin-1 (IL1) released from activated microglia is responsible for upregulating neuronal p38 mitogen activated protein kinase (p38 MAPK) and tau hyperphosphorylation via IL1-receptor (IL1-R) signaling pathway. In the current study, the effect of forebrain neuron specific ablation of IL1-R signaling via deletion of an IL1-R adopter protein, MyD88, on tau pathology, neurodegeneration and behavioral function will be studied in mouse models of systemic inflammation (via lipopolysaccharide) and in hTau mouse model of human tauopathy. The outcome of this study will explore the role of neuron-specific IL-1 signaling in tauopathies and provide mechanistic insights on utilizing neuronal IL-1R/MyD88 as a therapeutic target against human tauopathies.
|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|