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TDP-43 in AD/ADRD: Develop animal models (Milestone 4.V)

In Progress

Timeline Start - End

2020 - 2028

Research Implementation Area

Translational Tools, Infrastructure, and Capabilities

AD-Related Dementias Focus

Build new experimental models that incorporate aging with behavioral, pathologic, and molecular phenotypes of TDP-43 proteinopathy or hippocampal sclerosis, to advance knowledge and enable testing of therapeutics.

Success Criteria

  • Two or more validated animal models, available to the research community, that exhibit brain TDP-43 pathology aligned with the affected anatomical sites and with functional changes that occur in common human dementias that include TPD-43 pathology.

Summary of Key Accomplishments

TDP-43 neuropathology was not known to be significant in common dementias until recently. An important step toward understanding TDP-43's role in dementia and to identifying promising drug targets is to develop relevant animal models -- such models are a critical part of biomedical research because researchers are able to carry out experiments that would not be feasible or ethical in humans. Therefore, NIH is funding multiple projects to develop new animal models for TDP-43 pathology in dementia under two funding opportunity initiatives (PAR-19-167, RFA-NS-20-005). One funded research team has developed a new mouse model that carries a TDP-43-associated mutation (C9ORF72), and in a recent publication they showed that the mouse model develops accumulation of TDP-43 inside cells similar to that seen in humans with certain forms of dementia.

The key accomplishments summary is current as of July 2022.

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