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AD-Related Dementias Focus
Develop models to understand the pathophysiology and normal molecular and cellular functions of α-synuclein to support drug discovery.
2027 RFA-NS-19-013: Lewy Body Dementia Center Without Walls (CWOW) (U54) RFA-NS-21-006: Mechanisms of Pathological Spread of Abnormal Proteins in LBD and FTD (R01 Clinical Trial Not Allowed) RFA-NS-21-007: Mechanisms of Selective Vulnerability in LBD and FTD (R01 Clinical Trial Not Allowed) PAR-22-208: Structural Biology of Alzheimer's Disease Related Dementias (ADRDs) Proteinopathies (R01 Clinical Trial Not Allowed) PAR-23-154: Development and Validation of Models for Alzheimer’s Disease-Related Dementias (ADRD) (R61/R33 - Clinical Trial Not Allowed) PAR-24-234: Mechanistic Investigations into ADRD Associated Protein Structures in Biological Settings (R01 - Clinical Trial Not Allowed) RFA-NS-24-032: Development and Validation of Human Cellular Models for Alzheimer's Disease-Related Dementias (ADRD) (R01 - Clinical Trial Not Allowed) 2.T In Progress Understanding the molecular, cellular and α-synuclein in the context of non-motor brain areas. DN 2019 ADRD Summit: Lewy Body Dementias (LBD), Focus Area 2: Basic Science, Milestone 7 2022 ADRD Summit: Lewy Body Dementias (LBD) Milestone 7, Priority 3 News: A common marker of neurological diseases may play role in healthy brains Research on Disease Mechanisms Lewy Body Dementia Center Without Walls (CWOW) (U54) Select projects funded in FY21 Select projects funded in FY22
- At least three new projects designed both to understand and to compare normal and LBD-associated alpha synuclein biology.
- At least two new models of LBD that reproduce key features of LBD pathology and/or symptoms and are translatable for human LBD drug development.
Summary of Key Accomplishments
NINDS supported the creation and banking of multiple induced pluripotent stem cell (iPSC) lines from individuals with LBD that are now freely available to researchers through the NINDS Human Cell and Data Repository. A recently funded grant is refining a mouse model of LBD in which alpha-synuclein spreads from the gut to the brain as the animal ages, which is thought to occur in humans with LBD.
Similarly, in another mouse model that carries an alpha synuclein gene mutation, clumps of abnormal alpha synuclein were found in the brainstem at 4 months, and then at a greater distance away in the motor cortex at 8 months, following injection of alpha-synuclein in a leg muscle, again supporting the idea that alpha synuclein spreads via cell to cell connections over time.
Research in brain tissue from humans shows that particular cognitive abilities (executive and visuospatial) were impaired to a greater degree if abnormal alpha synuclein (Lewy bodies) was found in the cortex compared to brain tissue that had AD-related changes in the same brain regions.
The key accomplishments summary is current as of July 2022.