Characterization of a caspase-cleavage resistant tau knock-in mouse

Project Summary/Abstract Alzheimer?s Disease (AD) and related dementias are the most common cause of ageing-­ dependent dementia in the world and is associated with cerebral amyloid plaques and neurofibrillary tangles (NFTs). Current drug discovery approaches in AD and related dementias have focused on preventing formation or removing existing amyloid deposits. However, these approaches have so far failed and the most advanced alternative hypothesis is that of tau toxicity. Our preliminary data indicate that tau also mediates behavioral deficits in Familial Danish Dementia, an AD-­like dementia associated with mutations in the regulator of APP processing BRI2/ITM2B, also characterized by tauopathy. Some evidence suggests that caspases are activated early in the progression of AD and may play a role in neuronal loss and NFT pathology. Tau is cleaved at D421 by executioner caspases to generate ?Tau. Data in the literature suggest that ?Tau facilitates NFT formation and can exert toxic effects. In AD brains ?Tau associates with NFTs and correlates with cognitive decline. These findings have lead to the hypothesis that ?Tau is a critical toxic moiety underlying neurodegeneration. However, the published data are also compatible with the hypothesis that cleavage of tau by caspase could represent a negative feed-­back mechanism aimed to eliminate a toxic form of tau. To directly test these possibilities, we have generated knock-­in mice in which the endogenous tau codon GAC in exon 12, encoding for D421, has been mutated into AAC, which now encodes for an Asparagine (N). These knock-­in mice, called TauDN express a tau mutant, cannot be cleaved by caspases and therefore cannot generate ?Tau. TauDN mice will be used to determine whether ?Tau mediates synaptic plasticity and memory deficits in animal models of FDD and the related Familial British Dementia (FBD), two neurodegenerative disorders in which tau plays a pathogenic role. Our studies will speak to whether modulation of ?Tau formation is a potential strategy for the treatment of AD and other neurodegenerative disorders mediated by neuro-­toxic tau forms.