Evidence suggests that there is a bidirectional relationship between tau aggregation and inflammation in the aging brain. Both occur in all brains, and when present to a greater degree contribute to the neurodegenerative conditions termed tauopathies. The most well known of these is Alzheimer's disease, in which tau aggregates and their surrounding toxic biochemistry cause the widespread cell death and severe symptoms that characterize the final stages of the condition.
Various studies individually support each of the two directions of the relationship between tau and inflammation. Removing senescent cells from the brain dampens inflammatory signaling, and thereby reduces tau pathology, for example. Here, researchers demonstrate a mechanism by which tau aggregation encourages transposable element activity that in turn provokes an inflammatory response. We might view the later stages of many neurodegenerative conditions as runaway feedback loops in which inflammation produces consequences that encourage further inflammation.
Deposition of tau protein aggregates in the brain of affected individuals is a defining feature of "tauopathies," including Alzheimer's disease. Studies of human brain tissue and various model systems of tauopathy report that toxic forms of tau negatively affect nuclear and genomic architecture, identifying pathogenic tau-induced heterochromatin decondensation and consequent retrotransposon activation as a causal mediator of neurodegeneration. On the basis of their similarity to retroviruses, retrotransposons drive neuroinflammation via toxic intermediates, including double-stranded RNA (dsRNA).
We find that dsRNA and dsRNA sensing machinery are elevated in astrocytes of postmortem brain tissue from patients with Alzheimer's disease and progressive supranuclear palsy and in brains of tau transgenic mice. Using a Drosophila model of tauopathy, we identify specific tau-induced retrotransposons that form dsRNA and find that pathogenic tau and heterochromatin decondensation causally drive dsRNA-mediated neurodegeneration and neuroinflammation. Our study suggests that pathogenic tau-induced heterochromatin decondensation and retrotransposon activation cause elevation of inflammatory, transposable element-derived dsRNA in the adult brain.