Fyn - the missing link in the toxic triad of Alzheimer's disease.
Most people agree that the pathology of Alzheimer's disease (AD) is initiated by too much or abnormal AΒ42 peptide, which is made by cutting up the APP protein. Many of the toxic effects of AΒ42, particularly at the synapse, are mediated by tau, but only recently have clues to the links between AΒ42 and tau been found. It turns out that a key link is the tyrosine kinase called Fyn, and some now refer to the Toxic Triad - AΒ42/Fyn/tau. Fyn is a potential drug target for AD.
Fyn is a major control point for signalling from various G-protein linked receptors, such as dopamine D1, onto the NMDA receptor complex, where Fyn phosphorylation enhances the activity of GluN2B-containing receptors (Trepanier CH et al., 2012). Fyn phosphorylates the NR2 subunit of NMDA receptors, which makes the NMDAR complex interact better with PSD-95, the gateway to downstream "excitotoxic" effects. Some APP transgenic mice get seizures as well as AD symptoms. So Fyn has a central role in AΒ42 toxicity, and indeed reducing Fyn in APP transgenic mice prevents AΒ42 toxicity and seizures, while increasing Fyn makes it worse. So where does tau come in?
It turns out that tau is not just located in axons around microtubules, but also finds its way to dendrites and the postsynapse. Some shortened forms of tau don't make it to dendrites, however, and when that happens (or when there is no Tau at all), Fyn can't get to the postsynapse either (Ittner et al., 2010). So tau is needed to get Fyn to the postsynapse, where it can act to link AΒ42 effects to the NMDAR-driven excitotoxic cascade.
There's a lot more going on, and its not all completely understood. Tau interacts with the SH3 domain of Fyn, and is tyrosine-phosphorylated by Fyn on Tyr-18, which reduces tau-Fyn affinity. Disease-related phosphorylation and missense mutations of tau all increase the tau-Fyn interaction (Bhaskar et al., 2005). Tau Tyr-18 phosphorylation is increased by AΒ42 and leads to more tau getting into lipid rafts in membranes, where AΒ42 and its toxic soluble oligomers are also to be found. Strikingly, neurons of mice that don't have Fyn don't die from AΒ42 effects, and the AΒ42 doesn't make it into rafts (Williamson et al., 2008).
Fyn, AΒ42m and tau may be involved in regulating synapse and network function normally (Roberson et al., 2011). Fyn is just one of the human proteins which Brainwave-Discovery Ltd. is expressing in Drosophila synapses. We can help you find out the in vivo effects of your compounds on interactions of Fyn with its partners, within a normal or an Alzheimer's disease background. We also link in to a Europe-wide synaptic analysis network, SynSys (SynSys). For more information check out our website or contact firstname.lastname@example.org
- Bhaskar K., Yen, S-H and Lee, G 2005 J. Biol. Chem. 280, 35119-35125.
- Ittner, LM et al. 2010 Cell 142, 387-397
- Roberson ED, 2011 J. Neurosci. 31, 700-711
- Trepanier CH et al 2012 FEBS Journal 279, 12-19
- Williamson, R. et al., 2008 FASEB J. 22, 1552-9.