Tauopathies are a class of neurodegenerative diseases characterized by the aggregation of tau proteins in neurofibrillary tangles in the human brain. These proteins are associated to microtubules and are found mostly in neurons; their main function is to modulate the stability of axonal microtubules.

When hyperphosphorylated, tau proteins dissociate from the microtubule, aggregate and accumulate in insoluble neurofibrillary tangles (NFTs). NFTs represent the hallmark of tauopathies, Alzheimer’s disease (AD) among them. Although AD is the most common tauopathy, it is considered a secondary one, because tau protein accumulation is only one of the hallmarks of AD, along with beta amyloid plaques and neuronal loss (1).

It is recognized in AD that neuroinflammatory processes are critical in disease development and progression. Amyloid-beta (Aβ) activates the NLRP3 inflammasome, an intracellular protein complex comprised of NLRP3, ASC and caspase-1 that ispresent in innate immune cells and responsible for the activation of inflammatory responses. Indeed, levels of active cleaved caspase-1 are elevated in amyloid plaques in both mice and patients with AD, and NLRP3 knockout ameliorates amyloid plaque pathology in mice (2,3).

While the activity of microglia ─ the myeloid cells specific to the brain containing the inflammasome ─ has been firmly linked to amyloid plaque development, their relationship to tau tangles is still evading scientists.

An article published in the November 20th issue of Nature is about to change all that.

NRLP3 has a Role in Tauopathies

Dr. Michael Heneka and colleagues at the German Center for Neurodegenerative Diseases in Bonn hypothesized a potential role of the NLRP3 inflammasome in patients with tauopathies. The team used a combination of conventional protein detection methods, behavioral analysis and the nCounter® Mouse Neuroinflammation gene expression panel to find compelling evidence suggesting that microglial inflammation triggered by activation of the inflammasome prompts tau toxicity as well as plaque formation.

First, the authors established a role of NLRP3 inflammasome in tauopathies by analyzing cortical samples from patients with frontotemporal dementia ─ a primary tauopathy ─ and the brains of a mouse model of human tauopathies. They found elevated cleavage of caspase-1, increased ASC levels and mature pro-inflammatory cytokine IL-1β, indicative of NLRP3 inflammasome activation. 

NRLP3 has a Role in Tau Hyperphosphorylation

In an NLRP3-inflammasome-deficient mouse model, the authors found lower levels of cleaved caspase-1 and IL-1β as well as lower levels of tau hyperphosphorylation in the hippocampus. Additionally, they found reduced tau aggregations and less misfolded tau in the soluble fractions of hippocampal tissue from NLRP3-inflammasome-deficient mice. The loss of NLRP3 inflammasome components rescued the spatial memory deficits present in mice (4). The authors also found decreased levels of the inactive phosphatase PP2A accompanied by lower levels of its negative regulator PME-112 in hippocampal samples of NLRP3 deficient mice, suggesting that NLRP3 may regulate kinases and phosphatases.

This seminal paper places NLRP3 activation upstream of tau pathologies and establishes the induction of tau hyperphosphorylation and aggregation mediated by NLRP3 activation, providing a pathway that could be potentially targeted by NLRP3 inhibitors. Furthermore, since NLRP3 activation mediates Aβ-induced tau pathology, patients with Alzheimer’s disease may potentially benefit from NLRP3-directed treatment strategies.

The NanoString® Neuroinflammatory Panels

In this paper the gene expression analysis implemented using NanoString® Mouse Neuroinflammation Panel on the nCounter® Platform was employed to assess mechanisms of action throughout the study, and ultimately allowed the authors to extend observations made using other techniques to biologically meaningful conclusions that guided their next steps in the study. Moreover, they are now influencing the way the community views the role of microglia in Alzheimer’s pathogenesis.

Enjoy this groundbreaking paper by Ising and Heneka et al. and praised by leaders in the field such as Hugh Perry of the University College in London, Dave Morgan from Michigan State University, and Marco Colonna of the Washington University School of Medicine.

https://www.nature.com/articles/s41586-019-1769-z

References

  1. Serrano-Pozo A. et al, Neuropathological Alterations in Alzheimer Disease. Cold Spring Harb Perspect Med. 2011 Sep; 1(1): a006189.
  2. Halle, A. et al. The NALP3 inflammasome is involved in the innate immune response to amyloid-beta. Nat. Immunol. 9, 857–865 (2008).
  3. Heneka, M. T. et al. NLRP3 is activated in Alzheimer’s disease and contributes to pathology in APP/PS1 mice. Nature 493, 674–678 (2013).
  4. Schindowski, K. et al. Alzheimer’s disease-like tau neuropathology leads to memory deficits and loss of functional synapses in a novel mutated tau transgenic mouse without any motor deficits. Am. J. Pathol. 169, 599–616 (2006).

Posted by Laura Tabellini