NIH R01: Mechanistic Investigations into ADRD Associated Protein Structures in Biological Settings

Funding Opportunity Number: PAR-24-234

Deadline: October 4, 2024

Purpose/Research Objectives

Goal 1 of the National Plan to Address Alzheimer’s Disease is to prevent and effectively treat Alzheimer’s disease (AD) and Alzheimer’s Disease Related Dementias (ADRD). ADRDs include Frontotemporal dementia (FTD), Vascular Contributions to Cognitive Impairment and Dementia (VCID), Lewy Body Dementias (LBD) and Multiple Etiology Dementias (MED) based on similarities in clinical symptoms and brain pathologies between these and pathologcial AD and/or clinical AD. Starting in 2012, the National Institute on Aging (NIA) and the National Institute of Neurological Disorders and Stroke (NINDS) have held research summits to assess the needs and set AD/ADRD research implementation milestones. The NINDS ADRD Summit in 2022 resulted in ADRD research priorities for advancing the state-of-the-science toward meeting Goal 1 of the National Plan. This NOFO is responsive to several high priority milestones established at the 2022 ADRD Summit (, including improving the knowledge on pathological AD/ADRD proteins by characterizing them biochemically and biophysically to determine their unique features of specific strains in their cellular environment. Understanding the regulation of the protein levels and their aggregation, as a product of both regulation of expression, misfolding, and clearance will be important for preventing and treating AD/ADRD.

The field has made significant progress in identifying several potential pathogenic pathways leading to AD/ADRD, yet effective early-stage diagnosis and therapeutics are still lacking. While recent protein structures open the door for the design of tools like specific positron emission tomography (PET) ligands as well as many other potential applications, much work remains. For example, structures for several AD/ADRD proteinopathies remain to be determined. Whether the AD/ADRD proteinopathy structures currently available faithfully replicate what is found in various in vivo models and human patients remains unknown in many cases. Most molecular structures used for the design and development of tools for diagnosis are obtained by purifying samples from cells or tissues, and it is often assumed that the seeding conformation of the isolated proteins is faithfully propagated, however recent in situ structural evidence indicates that this may not always be the case. The conformations that proteins adopt are highly dependent upon differences in the cellular environment and understanding which conformations are adopted in healthy and pathological environment is critical to advancing the development of tools like PET ligands that better identify and monitor the accumulation of misfolded proteins in patients, as well as for other diagnostic, treatment response, and therapeutic development purposes. Derived structures of purified AD/ADRD proteins relies upon class averaging which biases the structure towards the dominant conformation in in-vitro experimental settings and this may not report on the diversity of physiological relevant conformations that exist in cells. Mechanistic studies under this NOFO should focus on pursuing the knowledge of which AD/ADRD protein structures are adopted in biological environment as well as their prevalence in disease.

The proposed study should capitalize on and/or develop methodologies for in cell (in-situ) structural approaches to determine high-resolution structures of AD/ADRD proteins, revealing distinct disease-specific conformations, understanding the evolution of the structures and their relative prevalence as conformations are propagated in different pathological settings, post-translational regulation, and how the cellular environment alters the conformation, folding, assembling and aggregations. Given that changes in protein conformation are complex, pathogenic entities with significant heterogeneity in clinical presentation, disease course, and underlying pathology, it is essential that the methodologies/tools under development and proposed approaches should be able to identify, detect or recognize the actual pathological strains observed in the cellular environment. The ultimate goal is to determine and characterize the heterogeneity of AD/ADRD proteins in the cellular environment, and to utilize structural features that define pathology in sporadic and familial forms of disease to provide novel insight into pathogenesis, disease progression, neurodegeneration, and cognitive impairment.

For more information, please see the opportunity webpage.