Figure 1.

Neuronal phospho-signallingand tangle formation.

The figure shows a post-synaptic neuron with its nucleus. After stimulation of ion-channels and/or G protein-coupled receptors via neurotransmitters originating from the presynapse, phospho-signalling associated with long-term potentiation (activation of phosphorylation) or long-term depression (suppression of phosphorylation), including Ca²⁺-, MAPK, PI3K or cAMP-mediated signalling is activated/inhibited. This can lead to changes in the phosphorylation status of down-stream targets such as stathmin1 or 14-3-3 proteins, which may in turn induce an altered phosphorylation profile of tau protein that can eventually culminate in NFT formation. Neuronal cellular metabolism is also important in this process, where cell cycle signalling may lead to an increased phosphorylation of Cdk proteins affecting NFT formation. Phosphorylation defects in stathmin1, 14-3-3 and Cdk (such as Cdk5) proteins have been shown to be involved in Alzheimer's neuropathology. cAMP: Cyclic adenosine monophosphate; Cdk: cyclin-dependent kinase; MAPK: mitogen-activated protein kinases; NFT: neurofibrillary tangles; PI3K: phosphoinositide 3-kinase. The figure was generated by images from commercial software (http://www.visiscience.com).