PROJECT SUMMARY
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-1ß (IL-1ß) 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-1ß in microglia.
Strikingly, suppression of pTau in vivo, microglial-specific deletion of MyD88 or ASC, significantly reduced IL-1ß
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-1ß 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-1ß 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-1ß 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-1ß pathway. This will of high significance
for the development and testing of the VLP-based pTau-targeted therapeutics against neuroinflammation in
tauopathies.