Abolishing Tau cleavage by caspases at Aspartate421 causes memory/synaptic plasticity deficits and pre-pathological Tau alterations

Abstract

TAU mutations are genetically linked to fronto-temporal dementia (FTD) and hyper-phosphorylated aggregates of Tau form neurofibrillary tangles (NFTs) that constitute a pathological hallmark of Alzheimer disease (AD) and FTD. These observations indicate that Tau has a pivotal role in the pathogenesis of neurodegenerative disorders. Tau is cleaved by caspases at Aspartate 421 , to form a Tau metabolite known as δTau; δTau is increased in AD, due to the hyper-activation of caspases in AD brains. δTau is considered a critical toxic moiety underlying neurodegeneration, which initiates and facilitates NFT formation. As Tau is a therapeutic target in neurodegeneration, it is important to rigorously determine whether δTau is a toxic Tau species that should be pharmacologically attacked. To directly address these questions, we have generated a knock-in (KI) mouse called Tau DN -that expresses a Tau mutant that cannot be cleaved by caspases. Tau DN mice present short-term memory deficits and synaptic plasticity defects. Moreover, mice carrying two mutant Tau alleles show increased total insoluble hyper-phosphorylated Tau in the forebrain. These data are in contrast with the concept that δTau is a critical toxic moiety underlying neurodegeneration, and suggest that cleavage of Tau by caspases represents a negative feedback mechanism aimed to eliminate toxic Tau species. Alternatively, it is possible that either a reduction or an increase in δTau leads to synaptic dysfunction, memory impairments and Tau pathology. Both possibilities will have to be considered when targeting caspase cleavage of Tau in AD therapy.

A role for tau in learning, memory and synaptic plasticity

“…At any rate, of the evidence that our mouse model reproduced some of the phenotypes already reported 39 , 42 – 44 supports a role of tau in learning, memory and synaptic plasticity. Moreover, recent data showing that caspase cleavage of tau at Asp 421 is essential for normal memory and normal LTP 59 further underline this important role of tau. In future studies it will be important to further test the role of tau in cognition and synaptic plasticity –for example to determine how early LTP is compromised by tau deletion- and to determine whether the effect of ablating tau expression is similar in both sexes.…”

Caspase-6-cleaved Tau fails to induce Tau hyperphosphorylation and aggregation, neurodegeneration, glial inflammation, and cognitive deficits

“…[45][46][47][48] ). Mice expressing endogenous Tau non-cleavable at D421 unexpectedly show Tau hyperphosphorylation, memory impairment, and synaptic plasticity deficits, indicating that TauΔD421 could be beneficial in this model or that the D421N mutation altered Tau function 32 . However, our work contradicts studies implicating TauΔD402/D421 in Tau aggregation and toxicity in AD brains [7][8][9][10][11][12][13] , transgenic animal models [24][25][26][27][28][29]31,49 , neuronal cells [17][18][19][20][21][22] , and recombinant proteins 7,23 .…”

“…Furthermore, TauC3 and TAU62 mice show memory impairments and synaptic alterations 28,29 . In contrast, transgenic mice expressing uncleavable D421 endogenous murine Tau exhibit long-term potentiation and cognitive deficits 32 .…”

Cleavage of human tau at Asp421 inhibits hyperphosphorylated tau induced pathology in a Drosophila model

“…It is also noteworthy that while the truncation of full-length tau at D421 translated into a distinct distribution of tau variant in the axonal terminal, the functional benefit towards the phospho-mimicking E14. In supporting this, a study found that the knock-in mutant with an abolished D421 cleavage site of mouse tau showed memory/synaptic plasticity defects 67 . Together with our result, it raises a possibility that, during the pathogenesis of tauopathy, if the hyperphosphorylated tau can be truncated at D421 at an earlier time point, it may reduce tau-induced neurotoxicity.…”