TDP-43 in AD/ADRD: Develop animal models (Milestone 4.V)
Timeline Start - End2020 - 2028
Research Implementation AreaTranslational 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.
- 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.
- PAR-19-167: Development and Validation of Advanced Mammalian Models for Alzheimer's Disease-Related Dementias (ADRD) (R61/R33)
- RFA-NS-20-005: Mechanistic Basis of TDP-43-dependent Pathobiology in Common Dementias (R01)
- RFA-NS-21-003: Center without Walls for Mechanisms of Neurodegeneration in Frontotemporal Dementia (FTD) (U54 Clinical Trial Not Allowed)
Research Programs and Resources
- Development and Validation of Advanced Mammalian Models for Alzheimer's Disease-Related Dementias (ADRD) (R61/R33)
- Select projects funded in FY21
- Select projects funded in FY22
- 2019 ADRD Summit: Emerging Scientific Topics, Focus Area 1: TDP-43 Pathology in Common Dementias, Milestone 4
- 2022 ADRD Summit: MED Special Topic: LATE (TDP-43 in Common Late-Onset Dementias) Milestone 3, Priority 3