Notice Number: NOT-AG-24-031
Expiration Date: November 17, 2027
Research Objectives
This NOSI encourages research to enhance our understanding of how different neurodegenerative diseases interact clinically and physiologically. There is a need to identify, more precisely, which neurodegenerative process, or processes, are active in individuals. At the same time, there needs to be better understanding of how different neurodegenerative diseases resemble and differ from one another at the molecular, cellular, and organismic levels. Cellular and animal models for investigating concurrent neurodegenerative processes need to be developed if these questions are to be answered.
Many neurodegenerative diseases involve aggregation and accumulation of misfolded proteins. Could they be studied as clinical variants of common cellular and molecular biological defects? At the same time, identifying pathophysiologic mechanisms unique to one neuropathologic entity, will be as informative as identifying commonalities.
Example research areas of interest appropriate to this NOSI include, but are not limited to, the following:
- Identify mechanisms for clearance of misfolded proteins and proteostasis, endoplasmic reticulum stress, and the unfolded protein response (e.g., proteasomes, lysosomes, autophagy).
- Define abnormal mitochondrial function regarding involvement in Parkinson’s Disease (a synucleinopathy), Huntington’s Disease, and Amyotrophic Lateral Sclerosis (ALS).
- Evaluate RNA transcription and processing in AD and AD-related dementias (ADRD).
- Examine the role of inflammation, microglial activation, and the innate immune system in AD and ADRD.
- Delineate the prion-like spread of alpha-synuclein and HPF-tau.
- Characterize the distinct “strains” of HPF-tau and alpha-synuclein.
- Identify the neurotoxic species related to AD, FTD, and LBD deposits of insoluble protein aggregates and soluble oligomers.
- The ApoE4 allele is a major genetic risk factor for both AD and LBD. How does a gene involved in lipid transport lead to increased beta-amyloid plaques, HPF-tau tangles, and alpha-synuclein Lewy Bodies?
- AD involves both beta-amyloid plaques and HPF-tau tangles. Neocortical beta-amyloid plaques are the earliest manifestation, but HPF-tau tangles are more closely associated with cognitive impairment. HPF-tau tangles in entorhinal cortex appear normally with age, and it appears that tau spread beyond entorhinal cortex requires the presence of beta-amyloid plaques. How do beta-amyloid plaques drive spread of HPF-tau tangles?
- HPF-tau is an important component of AD and a subtype of FTD (albeit with different mixes of isoforms). What else, besides beta-amyloid, distinguishes AD from other tauopathies?
- Examine cerebrovascular contributions to neurodegeneration as a shared mechanism across multiple diseases, including VCID, AD, and other neurodegenerative diseases.
- Develop experimental models of TDP-43 proteinopathies in its human context to faithfully model certain disease features.
- Develop models of TDP-43 proteinopathies that represent both nuclear loss of function and cytoplasmic accumulation toxic gain-of-function.
- Clarify pathogenic mechanisms that involve copathologies in AD by developing tools to model co-pathology of amyloid beta, tau, and TDP-43.
For more information, please see the announcement website.