4.5 Article

TDP-43 promotes tau accumulation and selective neurotoxicity in bigenic Caenorhabditis elegans

Journal

DISEASE MODELS & MECHANISMS
Volume 15, Issue 4, Pages -

Publisher

COMPANY BIOLOGISTS LTD
DOI: 10.1242/dmm.049323

Keywords

TDP-43; Tau; Amyloid beta (A beta); Caenorhabditis elegans; Alzheimer's disease; Proteotoxicity

Funding

  1. U.S. Department of Veterans Affairs Biomedical Laboratory Research and Development Service [I01BX004044]
  2. National Institutes of Health [K08AG065426, R01AG066729, R01NS064131]
  3. Nancy and Buster Alvord Endowment

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In addition to amyloid beta and tau, TDP-43 also plays a role in the pathology of Alzheimer's disease. TDP-43 enhances the neurotoxicity of tau, leading to cognitive decline and neurodegeneration. Studying this protein co-morbidity is crucial for understanding and treating mixed pathology Alzheimer's disease.
Although amyloid beta (A beta) and tau aggregates define the neuropathology of Alzheimer's disease (AD), TDP-43 has recently emerged as a co-morbid pathology in more than half of patients with AD. Individuals with concomitant A beta, 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 A beta, 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 Caenorhabditis elegans. We demonstrate that TDP-43 specifically enhances tau but not A beta 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 crucial to understand, and ultimately treat, mixed pathology AD.

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