Tale about Tau

Ashe KH. A Tale about tau. NEJM 2007;357:933-935.

The author reviews evidence suggesting that tau is an appropriate drug target for Alzheimer's disease. They cite a mouse model by Roberson ED et al (Science 2007;316:750-754)that expresses amyloid precursor protein encoded by two genes carrying two mutations for early onset familial AD. APP cleaves to form A Beta , the main component of amyloid plaques of AD, and the mice develop abnormal behaviors, memory loss and plaques. In these mice, depleting endogenous tau (from NFT's) (by crossing with mice in whom the tau gene was inactivated) , that did not result in decreased amyloid plaques in the mice, but did result in prevention of behavioral disturbance, memory loss and sudden death. Improvement occurred even with a 50 % reduction of tau. Soluble a Beta assemblies cause memory loss and bind to dendritic spines, the postsynaptic elements that house the key elements of memory formation. NFT's are not as important, as mice with neuritic plaques and tangles with reduced tau had normal behavior.

Tau joins other molecules that mediate the effects of aBeta on memory and synaptic plasticity. Tau lives in axons where it binds microtubules to polymerize and stabilize molecules. Under pathologic conditions, tau interacts with cytoskeletal component actin, mediating changes in dendritic spines and synaptic plasticity. Dendritic spines also are entry points for excitotoxicity.

Mice with low tau were resistant to excitotoxic seizures, suggesting it might potentiate excitotoxic effects of a Beta. Since tau facilitates brain dysfunction due to A Beta and excitotoxin, and even a partial low level can diminish bad effects, "propels tau to a higher spot" on list of therapeutic targets for Alzheimer's disease, and stroke and epilepsy (that involve excitotoxicity). Author cautions that TIMING of tau reduction may be important, as it may be important in development rather than in adult specimens.