Alzheimer's disease - a tau neurotoxicity mechanism conserved from flies to mammals
In the widely accepted amyloid cascade hypothesis of Alzheimer's disease causation, too much or the wrong structure of Abeta peptide initiates a set of biochemical changes, notably hyperphosphorylation of tau, which together lead to loss of neuronal function and death. Evidence from mouse models has shown that tau is essential for Abeta-induced NMDA dependent postsynaptic dysfunction (Ittner LM et al., 2010; Roberson ED et al., 2011), and suggests that Abeta causes synaptic dysfunction, but abnormal tau is required for neuronal death and severe cognitive decline (reviewed by Ashe KH and Zahs KR, 2010). However, the mechanism of tau neurotoxicity has remained obscure. Recently, work in Drosophila and mouse models of tau-mediated neurodegeneration has revealed at least part of the tau toxicity puzzle (DuBoff et al. 2012).
Before we look at how tau kills neurons, there is another important insight from this work - every detail of the molecular mechanism of tau toxicity is conserved from Drosophila to the mouse. These data dramatically confirm the relevance of the fly system for the discovery of drugs against Alzheimer's disease.
How does tau kill neurons? The evidence presented by DuBoff et al. suggests the following: hyperphosphorylated tau causes over-stabilisation of actin filaments, and excess F-actin leads to mislocalisation of a protein called DRP1. DRP1 is thus less able to get to the mitochondrial outer membrane when required, where it is needed to promote mitochondrial fission and maintain normal mitochondrial status. Neurons of flies and mice expressing too much wild type human tau, or a tau FTDP mutant, have longer mitochondria due to reduced localisation of DRP1 to mitochondria and reduced mitochondrial fission. There is a missing link here, but reducing mitochondrial fission is known to lead to increased ROS production and oxidative stress. This in turn leads to DNA damage, abnormal cell-cycle re-entry and apoptosis (Khurana et al., 2012). Increased ROS and apoptosis are in fact observed in these animal models.
It has been known for a while that hyperphosphorylated tau stabilises actin (Fulga et al., 2007), but it was not obvious how this could cause neuronal death, and most attention has been given to axonal transport of organelles, which is indeed reduced (Semenova et al., 2008, Kopeikina et al., 2011). This is still part of the story, since mitochondria are needed locally at synapses, but the disruption of mitochondrial fission control by tau is more important and is not dependent on transport failure. Mitochondrial fission, which DRP1 stimulates, seems to be needed to allow removal of dysfunctional mitochondrial membrane via autophagy (Twig et al., 2008). Clearly, not clearing out malfunctioning mitochondria will in the long term cause damage due to increased free radical production and oxidative stress.
Duboff et al. also used Drosophila genetics to reveal another molecular player in the tau toxicity mechanism - myosin II. The fly genes encoding the heavy chain and the regulatory light chain of myosin II are called Zipper (zip) and spaghetti squash (sqh) respectively. Flies heterozygous for loss of function mutants in these genes have longer mitochondria, reduced localisation of DRP1 to mitochondria - and increased tau toxicity. Exactly the same was found when mammalian myosin II light chain expression was knocked down by RNA interference in cultured cells. Most significantly, the association of mitochondria with F-actin was reduced in the myosin II fly mutants, suggesting that myosin II is important for linking mitochondria to actin, and thus to DRP1 and fission control.
These exciting insights into tau neurotoxicity open the way to new ideas for drug discovery. All the molecular components are the same, and are well conserved at the protein sequence level between flies and mammals. Flies are now viewed as a high-content, low-cost system for screening drugs.
Brainwave-Discovery Ltd. has Drosophila models of human wild type and mutant tau toxicity. Our established humanisation procedures allow the construction of new models expressing human DRP1 and human myosin II. We can help you screen your compounds for activity against tau-mediated neurodegeneration in Alzheimer's disease and other tauopathies. We also link in to a Europe-wide synaptic analysis network, SynSys). For more information check out our website or contact firstname.lastname@example.org
- Ashe K.H. and Zahs K.R., 2010, Neuron 66, 631-645.
- DuBoff B. et al., 2012, Neuron 75, 618-632.
- Fulga T.A. et al., 2007, Nature Cell Biology 9, 139-148.
- Ittner L.M. et al., 2010, Cell 142, 387-397.
- Kopeikina K.J. et al. ,2011, American Journal of Pathology 179, 2071-2082.
- Khurana V. et al., 2012, Aging Cell 11, 360-362.
- Roberson E.D., 2011, Journal of Neuroscience 31, 700-711.
- Semenova I. et al., 2008, Current Biology 18, 1581-1586.
- Twig G. et al., 2008, EMBO Journal. 27, 433-446.