RF1AG075992

NCRNAs in Plasma EVs of AD Patients and Their Discriminatory Power as Biomarkers

Alzheimer's disease is the most common and economically impactful form of dementia. Approaches based on cerebrospinal fluid and blood have been established to measure the levels of amyloid beta and hyperphosphorylated tau to facilitate early diagnosis of AD or to monitor the effects of therapeutics and progression of the disease.

Plasma extracellular vesicles (EVS) and their cargo present an opportunity to isolate and profile molecules associated with human pathological conditions. We have recently discovered small nucleolar non-coding RNAs (snoRNAs) highly enriched in plasma EVs of AD patients compared to non-demented controls. We posit that tau aggregates irreversibly bind snoRNAs, preventing them from performing their normal function, resulting in a compensatory increase of their expression in AD brains.

Our hypothesis is that the expression of certain snoRDs and their secretion in neuron-derived EVs is increased with the progression of AD. Small non-coding nucleolar snoRNAs might represent ideal biomarkers, compared with proteins and/or mRNAs, because of the protective effect of plasma EV and the unprecedented sensitivity of detection by ddPCR technology – down to single transcripts.

This proposal's primary goals are:

1) To test and validate the diagnostic accuracy of SNORD115 and SNORD116 ddPCR assays in human plasma;

2) To understand the nature of the associations between the abundance of particular snoRDs in AD plasma EVs, their expression level in the brain, the disease state and progression, and if there is an association with APOE genotype;

3) To test for epigenetic mechanisms underlying the changes in abundance of snoRDs; and

4) Using AD mouse models to reveal the effect of amyloid and tau aggregation on ISF, CSF, and plasma EVs cargo.

A better understanding of the underlying regulatory genomic, epigenomic, and cellular mechanisms responsible for the differences in the enrichment of snoRDs in plasma EVs of AD patients compared to controls would help understand essential aspects of APOE-mediated risk of AD and in establishing reliable diagnostic strategies.

University Of Pittsburgh - Of The Commonwealth System Of Higher Education

TO ENCOURAGE BIOMEDICAL, SOCIAL, AND BEHAVIORAL RESEARCH AND RESEARCH TRAINING DIRECTED TOWARD GREATER UNDERSTANDING OF THE AGING PROCESS AND THE DISEASES, SPECIAL PROBLEMS, AND NEEDS OF PEOPLE AS THEY AGE. THE NATIONAL INSTITUTE ON AGING HAS ESTABLISHED PROGRAMS TO PURSUE THESE GOALS. THE DIVISION OF AGING BIOLOGY EMPHASIZES UNDERSTANDING THE BASIC BIOLOGICAL PROCESSES OF AGING. THE DIVISION OF GERIATRICS AND CLINICAL GERONTOLOGY SUPPORTS RESEARCH TO IMPROVE THE ABILITIES OF HEALTH CARE PRACTITIONERS TO RESPOND TO THE DISEASES AND OTHER CLINICAL PROBLEMS OF OLDER PEOPLE. THE DIVISION OF BEHAVIORAL AND SOCIAL RESEARCH SUPPORTS RESEARCH THAT WILL LEAD TO GREATER UNDERSTANDING OF THE SOCIAL, CULTURAL, ECONOMIC AND PSYCHOLOGICAL FACTORS THAT AFFECT BOTH THE PROCESS OF GROWING OLD AND THE PLACE OF OLDER PEOPLE IN SOCIETY. THE DIVISION OF NEUROSCIENCE FOSTERS RESEARCH CONCERNED WITH THE AGE-RELATED CHANGES IN THE NERVOUS SYSTEM AS WELL AS THE RELATED SENSORY, PERCEPTUAL, AND COGNITIVE PROCESSES ASSOCIATED WITH AGING AND HAS A SPECIAL EMPHASIS ON ALZHEIMER'S DISEASE. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM: TO EXPAND AND IMPROVE THE SBIR PROGRAM, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM: TO STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION.

93.866 - Aging Research

National Institute on Aging (NIA) [HHS - NIH]

Pittsburgh, Pennsylvania 15261 United States

Single Zip Code

Research on Current Topics in Alzheimer's Disease and Its Related Dementias (R01 Clinical Trial Optional) (PAR-19-070)

Amendment Since initial award the End Date has been extended from 08/31/25 to 08/31/27 and the total obligations have increased 63% from $2,297,526 to $3,734,887.