Two hallmarks of Alzheimer’s—amyloid-β pathology and tau pathology—are linked by a protein complex, the NLRP3 inflammasome. When amyloid-β deposits form, they can activate the NLRP3 inflammasome, causing the formation of additional amyloid-β deposits, which accumulate between neurons. Worse, the NLRP3 inflammasome can proceed to “hyperphosphorylate” tau proteins, causing them to aggregate within neurons. Essentially, the NLRP3 inflammasome delivers a one-two punch.

This pugilistic combination has been reported by scientists based at the German Center for Neurodegenerative Diseases (DZNE) and the University of Bonn. The scientists, led by Michael Heneka, MD, PhD, director of the department of neurodegenerative diseases and gerontopsychiatry at the University of Bonn and a senior researcher at the DZNE, arrived at their findings after examining tissue samples from the brains of deceased frontotemporal dementia (FTD) patients. They also experimented with cultured brain cells and mice that exhibited hallmarks of FTD and Alzheimer’s. Crucial to the scientists’ work was a comparison of mice in which NLRP3 inflammasome function was intact, and mice in which it was eliminated.

Detailed findings appeared November 20 in Nature, in an article titled, “NLRP3 inflammasome activation drives tau pathology.” These findings, the article’s authors indicated, identify an important role of microglia and NLRP3 inflammasome activation in the pathogenesis of tauopathies. They also support the amyloid-cascade hypothesis in Alzheimer’s disease, demonstrating that neurofibrillary tangles develop downstream of amyloid-β-induced microglial activation.

“Loss of NLRP3 inflammasome function reduced tau hyperphosphorylation and aggregation by regulating tau kinases and phosphatases,” the article’s authors wrote. “Tau activated the NLRP3 inflammasome and intracerebral injection of fibrillar amyloid-beta-containing brain homogenates induced tau pathology in an NLRP3-dependent manner.”

The findings apply to “tauopathic” neurodegenerative diseases besides Alzheimer’s. In the case of Alzheimer’s, however, the accumulation of amyloid-β comes into play. Typically, the inflammasome-driven accumulation of amyloid-β occurs before tau aggregation.

“Our results support the amyloid cascade hypothesis for the development of Alzheimer’s,” noted Heneka. “According to this hypothesis, deposits of amyloid-β ultimately lead to the development of tau pathology and thus to cell death.

“The inflammasome is the decisive and hitherto missing link in this chain of events, because it bridges the development from amyloid-β pathology to tau pathology. It passes the baton, so to speak.”

In particular, the researchers discovered that the inflammasome influences enzymes that induce a hyperphosphorylation of tau proteins, which usually stabilize a neuron’s skeleton. The hyperphosphorylation ultimately causes the tau proteins to separate from the scaffold of neurons and clump together. As a consequence, the cell’s mechanical stability is compromised to such an extent that it dies off.

“It appears, Heneka stressed, “that inflammatory processes mediated by the inflammasome are of central importance for most, if not all, neurodegenerative diseases with tau pathology.”

“Tau oligomers and fibrils, but not monomers, have previously been shown to promote tau pathology and neuronal degeneration in assays with direct application of tau species on neuronal cultures,” the authors of the Nature article indicated. “Here we provide evidence that tau oligomers and monomers have direct effects on microglia by activating NLRP3. As nonfibrillar tau can actively be released by neurons, it could thereby contribute to chronic microglial activation in tauopathies.”

With these findings, the neuroscientist sees opportunities for new treatment methods. “The idea of influencing tau pathology is obvious,” Heneka stated. “Future drugs could tackle exactly this aspect by modulating the immune response.” For example, the tauopathic pathway could be blocked by NLRP3 inhibitors or by inhibition of tau binding to microglia.

“With the development of tau pathology, mental abilities decline more and more,” Heneka emphasized. “Therefore, if tau pathology could be contained, this would be an important step toward a better therapy.”

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