The primary goal of this project is to determine whether pathological forms of tau (pTau) ? a significant pathological hallmark of neurodegenerative tauopathies, can activate interleukin-1b (IL-1b) through MyD88- dependent nuclear factor-kB (NF-kB) and NLRP3-ASC inflammasome pathway to cause neuroinflammation, axonal and white matter pathology, synaptic loss and cognitive impairment. The goal is also to test the efficacy of a novel pTau-targeted virus-like particle (VLP)-based immunotherapy strategy against pTau-induced neuroinflammation in hTau model of tauopathy. Recent studies have suggested that once tau is hyperphosphorylated and misfolded, the neurons tend to expel pTau to the extracellular space, which is taken up by other neurons and results in trans-neuronal propagation of pTau. We made a compelling discovery that en route to other neurons, pTau can also interact with and serve as an initial trigger to lead to microglial activation and neuroinflammation. However, it is not clear how exactly pTau can induce innate immune activation within microglia. Our preliminary results suggest the possibility that neuronally-derived pTau upregulates microglial cell surface receptors like toll-like receptors (TLRs), engage MyD88 (a key adapter protein common for various TLRs and IL-1Rs), activate NF-kB and NLRP3-ASC inflammasomes and lead to maturation of IL-1b in microglia. Strikingly, suppression of pTau in vivo, microglial-specific deletion of MyD88 or ASC, significantly reduced IL-1b maturation. Intriguingly, clearing pTau via VLP-based vaccine reduces MyD88 expression, neuroinflammation, tau pathology and improves memory. Based on these preliminary observations we hypothesize that pTau activates NF-kB-NLRP3-ASC inflammasomes-IL-1b innate immune complex through TLR/MyD88-dependent pathway in microglia. Targeting pTau (by VLP-based immunotherapy), MyD88 or IL-1R1 accessory protein (IL- 1RAcP) at different levels of this cascade blocks the feed-forward induction of brain inflammation induced by tau. We will test this hypothesis under three Specific Aims. In the Specific Aim 1, we propose to determine if different forms of pTau from post-mortem human brains trigger NF-kB priming by MyD88 and IL-1b maturation by NLRP3-ASC-inflammasomes pathways.
In Specific Aim 2, we propose to determine if pTau-induced progressive NF-kB activation, neuroinflammation, MRI-based structural alterations and cognitive dysfunction is MyD88/IL-1RAcP dependent in hTau mouse model of tauopathy. Finally, in Specific Aim 3, we will determine if blocking pTau by VLP-based immunotherapy reduces NF-kB priming and IL-1b maturation as well as restore memory in hTau mice. This successful outcome of this study will determine whether pTau triggers neuroinflammation via MyD88-NF-kB-NLRP3-ASC inflammasomes-IL-1b pathway. This will of high significance for the development and testing of the VLP-based pTau-targeted therapeutics against neuroinflammation in tauopathies.

Public Health Relevance

This project addresses several issues of central importance to all tauopathies. A) the neuroinflammation often observed in the same brain regions that show aggregation of hyperphosphorylated pathological forms of tau (pTau). B) neurons secrete pTau into the extracellular space which has the likelihood of serving as ?danger signal? to activate microglia and eventually causing neuroinflammation. However, it is unclear how do neuron- intrinsic pTau could contribute to the brain inflammation? Our preliminary results indicate that pTau causes neuroinflammation by activating NF-kB and inflammasomes within microglia and lead to the maturation/secretion of interleukin-1b (IL-1b). The NF-kB activation seem to depend on the recruitment of a universal adapter protein called myeloid differentiation primary response 88 (MyD88) and maturation of IL-1b seem to occur through inflammasomes containing Apoptosis-associated speck-like protein containing a CARD (ASC) within microglia. Based on these preliminary findings, we propose to perform neuropathological analysis in human tauopathy samples, develop and test the effects of different forms of pTau on MyD88/NF-kB/ASC/IL-1b pathway in human primary microglia (in Aim 1). We propose to perform longitudinal measurement of NF-kB activation and MRI analysis in hTau mouse model of tauopathy expressing NF-kB reporter and with microglia-restricted deletion of MyD88 and IL- receptor accessory protein (IL-1RAcP) (Aim 2). Final set of analysis will test if neutralizing antibodies generated via our virus-like particle (VLP) based immunotherapy against pTau would block MyD88 recruitment, NF-kB and inflammasome activation as well as IL-1b maturation in hTau mice. The successful outcome of this study will conclusively establish how pTau drives local and chronic neuroinflammation pertinent to tauopathies. It also tests the VLP-based vaccines targeting pTau against tauopathies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
2R01NS083704-05A1
Application #
9887762
Study Section
Cell Death in Neurodegeneration Study Section (CDIN)
Program Officer
Mcgavern, Linda
Project Start
2020-03-01
Project End
2025-02-28
Budget Start
2020-03-01
Budget End
2021-02-28
Support Year
5
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of New Mexico Health Sciences Center
Department
Genetics
Type
Schools of Medicine
DUNS #
829868723
City
Albuquerque
State
NM
Country
United States
Zip Code
87131
Raz, Limor; Bhaskar, Kiran; Weaver, John et al. (2018) Hypoxia promotes tau hyperphosphorylation with associated neuropathology in vascular dysfunction. Neurobiol Dis :
Bemiller, Shane M; Maphis, Nicole M; Formica, Shane V et al. (2018) Genetically enhancing the expression of chemokine domain of CX3CL1 fails to prevent tau pathology in mouse models of tauopathy. J Neuroinflammation 15:278
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
Kokiko-Cochran, Olga; Ransohoff, Lena; Veenstra, Mike et al. (2016) Altered Neuroinflammation and Behavior after Traumatic Brain Injury in a Mouse Model of Alzheimer's Disease. J Neurotrauma 33:625-40
Raz, Limor; Knoefel, Janice; Bhaskar, Kiran (2016) The neuropathology and cerebrovascular mechanisms of dementia. J Cereb Blood Flow Metab 36:172-86
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
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
Chauhan, Santosh; Ahmed, Zahra; Bradfute, Steven B et al. (2015) Pharmaceutical screen identifies novel target processes for activation of autophagy with a broad translational potential. Nat Commun 6:8620