The accumulation of hyperphosphorylated tau is associated with several neurodegenerative disorders, including Alzheimer's disease, fronto-temporal dementia and Pick's disease, and is suspected to contribute to the pathogenesis of such conditions, although the mechanisms by which it does this are unknown. Feany and colleagues now provide evidence that tau can mediate neurodegeneration through interactions with actin.
Previous in vitro studies have revealed interactions between the microtubule-associated protein tau and actin, and separate studies have suggested that actin aggregation can trigger cell death. Actin-rich inclusions have been found in the brains of patients with various neurodegenerative conditions. However, it is not known whether these interactions can cause neurodegeneration in vivo. To investigate this question, the authors used several strains of transgenic Drosophila melanogaster that expressed wild-type human tau or a mutant form of tau associated with familial fronto-temporal dementia.
Flies in which mutant tau was expressed in all neurons had increased levels of filamentous actin, a proportion of which was associated with tau, demonstrating that neuronal tau and actin interact in this model. The flies' brains also contained rod-shaped, actin-rich inclusions, many of which were positive for phosphorylated tau. Similar results were observed in transgenic mice expressing mutant tau, in which actin-rich inclusions were observed in several brain regions.
To explore further the interactions between tau and actin, double transgenic flies were created, in which expression of a mutant or wild-type tau was targeted to the retina in conjunction with a transgene expressing actin. In flies expressing mutant tau, retinal toxicity was observed; however this was dramatically increased in flies co-expressing actin. Manipulating the actin cytoskeleton, by co-expressing a gene that destabilizes actin filaments, or by knocking out actin completely, reduced tau-induced retinal damage.
These findings indicated that tau and actin can interact to cause neurotoxicity, perhaps through the stabilization and aggregation of actin filaments. When mutant tau and actin were overexpressed in all neurons, there was an increase in filamentous actin and actin-rich inclusions in the brain, which correlated with levels of neurodegeneration. Wild-type tau did not produce these effects, suggesting that mutated tau has a greater capacity to interact with actin to cause neurodegeneration. Modifying actin did not alter tau phosphorylation, suggesting that the stabilization and aggregation of actin filaments is downstream of tau in the pathogenic pathway. Furthermore, when a mutated form of tau that mimics phosphorylation at disease-associated sites was expressed, toxicity was increased, which is associated with increased levels of filamentous actin and actin aggregation.
It is unknown whether the actin-rich inclusions observed in the brain contribute to the disease pathology, or instead represent an attempt by neurons to protect themselves from accumulating potentially toxic actin filaments. Nevertheless, this study provides in vivo evidence for an interaction between hyperphosphorylated tau, modification of the actin cytoskeleton and neurotoxicity. It will be important to test these findings in other in vivo models and further work will be needed to identify the pathogenic events that are downstream of this interaction.