While amyloid (A) β and tau aggregates define the neuropathology of Alzheimer's disease (AD), TDP-43 has recently emerged as a co-morbid pathology in over half of patients with AD. Individuals with concomitant Aβ, tau, and TDP-43 pathology experience accelerated cognitive decline and worsened brain atrophy, but the molecular mechanisms of TDP-43 neurotoxicity in AD are unknown. Synergistic interactions among Aβ, tau, and TDP-43 may be responsible for worsened disease outcomes. To study the biology underlying this process, we have developed new models of protein co-morbidity using the simple animal C. elegans. We demonstrate that TDP-43 specifically enhances tau but not Aβ neurotoxicity, resulting in neuronal dysfunction, pathological tau accumulation, and selective neurodegeneration. Furthermore, we find that synergism between tau and TDP-43 is rescued by loss-of-function of the robust tau modifier sut-2. Our results implicate enhanced tau neurotoxicity as the primary driver underlying worsened clinical and neuropathological phenotypes in AD with TDP-43 pathology, and identify cell-type specific sensitivities to co-morbid tau and TDP-43. Determining the relationship between co-morbid TDP-43 and tau is critical to understand and ultimately treat mixed pathology AD.
TDP-43 promotes tau accumulation and selective neurotoxicity in bigenic C. elegans
- Award Group:
- Funder(s): National institutes of health
- Award Id(s): K08AG065426
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- Award Group:
- Funder(s): Nancy and Buster Alvord Endowment
- Funder(s):
- Award Group:
- Funder(s): U.S. Department of Veterans Affairs
- Award Id(s): I01BX004044
- Funder(s):
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Caitlin S. Latimer, Jade G. Stair, Joshua C. Hincks, Heather N. Currey, Thomas D. Bird, C. Dirk Keene, Brian C. Kraemer, Nicole F. Liachko; TDP-43 promotes tau accumulation and selective neurotoxicity in bigenic C. elegans. Dis Model Mech 2022; dmm.049323. doi: https://doi.org/10.1242/dmm.049323
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