Basic Science and Pathogenesis.

Background: TDP-43 proteinopathy, initially discovered in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), coexists with tauopathy in a variety of neurodegenerative disorders, including Alzheimer's Disease (AD). While such co-pathology is strongly associated with worsened neurodegeneration and steeper cognitive decline, how these two pathologies influence each other to exacerbate neuron loss remains elusive. That loss of TDP-43 splicing repression occurring in presymptomatic ALS-FTD suggests that loss of TDP-43 function could facilitate the pathological conversion of tau to accelerate tauopathy and neuron loss.

Method: To elucidate how loss of TDP-43 function influence tauopathy, we used two complementary approaches to express a four-repeat domain fragment of human tau (hTauRD) to seed tauopathy in CaMKII-CreER;Tardbp mice: 1) inducible transgenesis; and 2) intraparenchymal delivery of an adeno-associated viral vector unilaterally in the hippocampus.

Results: Here, we found that depletion of TDP-43 is sufficient to activate caspase 3-dependent cleavage of tau and cell death of vulnerable neurons, such as those in CA3/2 of the hippocampus, in mice lacking TDP-43 in their forebrains (CaMKII-CreER;Tardbp mice). To establish this mechanistic insight that the level of activated caspase 3-dependent cleavage of tau may determine the vulnerability of neurons in AD cases harboring the co-pathology of TDP-43, we elevated levels of hTauRD in CaMKII-CreER;Tardbp mice to stimulate the activation of caspase 3. As compared to age-matched controls, we show an additive impact of TDP-43 loss-of-function and hTauRD to promote further increase of activated caspase 3 to elevate the cleavage of endogenous tau, thereby accelerating death of cells to also include neurons of the dentate gyrus and/or CA1.

Conclusion: Taken together with previous results documenting that activated caspase 3-dependent cleavage of tau occurs in cases of AD and their mouse models, our findings strongly support the view that TDP-43 loss-of-function accelerates tauopathy in vulnerable neurons by promoting caspase 3-mediated endoproteolytic cleavage of tau, thereby exacerbating neuron loss in neurodegenerative disorders harboring co-pathologies of tau and TDP-43, and disclose for these human diseases a potential therapeutic target to attenuate neuron loss.