The early stage of Alzheimer’s disease is characterized by the slowly increasing aggregation of amyloid-β into solid deposits, something that may occur due to failing clearance of metabolic waste from the brain via drainage paths for cerebrospinal fluid. The complex biochemistry surrounding amyloid-β is damaging to the operation of brain cells, but not damaging enough to cause more than mild cognitive impairment in and of itself. Unfortunately, the presence of amyloid-β also in some way creates the foundation for the second stage of the condition, in which a modified form of tau protein forms aggregates known as neurofibrillary tangles. These aggregates and their surrounding biochemistry are far more harmful, causing major neural dysfunction and cell death in the ultimately fatal end stages of Alzheimer’s disease.
How does amyloid-β aggregation cause tau aggregation? The answer is unlikely to be simple, and unlikely to involve only one mechanism, as little in biochemistry is anything other than complicated. There is a good deal of evidence to suggest that chronic inflammation and associated dysfunction of immune cells such as microglia in the central nervous system are important bridging mechanisms between amyloid-β and tau. For example, clearing out senescent microglia and thus reducing neuroinflammation turns back tau aggregation in mouse models. Given present progress in senolytic therapies, it won’t be too long now before the research community finds out how well this approach does in humans.
What about other mechanisms, however? Today’s research suggests that amyloid-β disrupts the normal activity of tau in a previously unsuspected way. Tau is a normally a part of the cellular cytoskeleton, the microtubules that support cell structure. The presence of amyloid-β encourages another protein, cofilin, to disrupt the microtubules and thus free up tau from its usual location and behavior. The evidence from mice in this study supports the view that this process is important in the generation of the altered forms of tau that eventually form neurofibrillary tangles. How does this process interact with neuroinflammation and bad behavior on the part of microglia? That remains to be determined.
The two primary hallmarks of Alzheimer’s disease are clumps of sticky amyloid-beta (Aβ) protein fragments known as amyloid plaques and neurofibrillary tangles of a protein called tau. Abnormal accumulations of both proteins are needed to drive the death of brain cells, or neurons. But scientists still have a lot to learn about how amyloid impacts tau to promote widespread neurotoxicity, which destroys cognitive abilities like thinking, remembering and reasoning in patients with Alzheimer’s. While investigating the molecular relationship between amyloid and tau, neuroscientists have now discovered that the Aβ-activated enzyme cofilin plays an essential intermediary role in worsening tau pathology.
The research introduces a new twist on the traditional view that phosphorylation of tau is the most important early event in tau’s detachment from brain cell-supporting microtubules and its subsequent build-up into neurofibrillary tangles. These toxic tau tangles disrupt brain cells’ ability to communicate, eventually killing them. Without microtubules, axons and dendrites could not assemble and maintain the elaborate, rapidly changing shapes needed for neural network communication, or signaling. Tau molecules are like the railroad track ties that stabilize and hold train rails (microtubules) in place.
Using a mouse model for early-stage tauopathy, researchers showed that Aβ-activated cofilin promotes tauopathy by displacing the tau molecules directly binding to microtubules, destabilizes microtubule dynamics, and disrupts synaptic function – all key factors in Alzheimer’s disease progression. Unactivated cofilin did not. The researchers also demonstrated that genetically reducing cofilin helped prevent the tau aggregation leading to Alzheimer’s-like brain damage in mice. “Our data suggests that cofilin kicks tau off the microtubules, a process that possibly begins even before tau phosphorylation. That’s a bit of a reconfiguration of the canonical model of how the pathway leading to tauopathy works.”
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and the most common form of dementia. While the accumulation of Aβ is pivotal to the etiology of AD, both the microtubule-associated protein tau (MAPT) and the F-actin severing protein cofilin are necessary for the deleterious effects of Aβ. However, the molecular link between tau and cofilin remains unclear. In this study, we found that cofilin competes with tau for direct microtubule binding in vitro, in cells, and in vivo, which inhibits tau-induced microtubule assembly. Genetic reduction of cofilin mitigates tauopathy and synaptic defects in Tau-P301S mice and movement deficits in tau transgenic C. elegans. The pathogenic effects of cofilin are selectively mediated by activated cofilin, as active but not inactive cofilin selectively interacts with tubulin, destabilizes microtubules, and promotes tauopathy. These results therefore indicate that activated cofilin plays an essential intermediary role in neurotoxic signaling that promotes tauopathy.