R01AG076949

New Technologies to Identify Molecular Regulators of the Human Hippocampus Neurogenic Niche in Healthy Aging and Alzheimer's Disease

The hippocampus neurogenic niche (HNN) generates new neurons in mammals, but it is unclear if this is happening in humans. Adult hippocampal neurogenesis is necessary to maintain intact cognitive and emotional functions regulated by the hippocampus. Markers of immaturity have been detected in neuronal cells of the HNN, but it is still unclear if they represent adult-born neurons or neuronal cells that have maintained their immaturity since birth.

We found that the number of neural progenitor cells (NPCs) and immature neurons was stable throughout the eighth decade of life in normal aging (NA) subjects, but angiogenesis and neuroplasticity were decreased in older people. Other groups have supported our findings, while some could not detect immature neuronal cells in the human hippocampus. Moreover, in aging mice, more NPCs differentiate into glia rather than neurons, compared to younger animals, but we do not know if this happens in humans. Adult neurogenesis is lower in Alzheimer's disease (AD), and it is unknown if this is because more NPCs differentiate into glia or through other mechanisms.

These gaps in knowledge warrant the use of new technologies to investigate cellular lineages in the human HNN and molecular regulators of NPCs proliferation, cell fate, differentiation, maturation, and survival. This project aims to identify differentially expressed proteins (DEPs) and genes (DEGs) in the human HNN, at the regional and single-cell level, comparing NA and AD. We will apply our pipeline using high-resolution mass spectrometry for proteomics analysis and single nuclei (SN) RNA and ATAC (Assay for Transposase-Accessible Chromatin) sequencing (Seq) to identify gene expression and epigenetic changes.

In slide-mounted hippocampus tissue, we will apply Visium (10x Genomics) and our custom-made spatial transcriptomic technology for anatomical co-mapping of cell-type-specific mRNAs and proteins (DBIT-Seq). Novel computational approaches will identify neurogenesis regulators in the human HNN that can be tested in cellular or animal models. Findings obtained with these "omics" approaches will be validated using Highplex RNAscope® (ACDBio) and immunofluorescence, as well as qPCR, Western blots, and ELISA assays, to visualize and quantify DEP and DEG expression at the single-cell and regional level.

Our rigorous brain collection methods assure tissue quality, uniform processing, use of toxicology and neuropathology, and strict clinical inclusion/exclusion criteria. Groups include: NA subjects (N=100), Braak stage 0-1, age 14-99 yrs., 40 of which (60 years of age and older) are matched (by age, sex, and postmortem interval between death and brain collection) with 40 AD cases (from the Columbia Taub Institute collection), Braak stage 1 through 4.

Aims:
1. Identify HNN DEPs associated with NA and AD.
2. Identify DEGs in immature and mature neuronal and glial cell populations of the DG in NA and AD subjects, using SN-RNA and SN-ATAC-Seq (10x Genomics).
3. Determine the anatomical localization of cells expressing DEGs and DEPs associated with NA and AD, using Visium and DBIT-Seq.
4. Test correlations between DEPs and DEGs and numbers of NPCs and immature neurons and glia in NA and AD.

Research Foundation For Mental Hygiene

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]

New York, New York 100321007 United States

Single Zip Code

New Approaches to Identify Neurogenesis and Study its Dynamics in Brain Aging and AD/ADRD (R01 Clinical Trial Not Allowed) (RFA-AG-22-006)

Amendment Since initial award the total obligations have increased 330% from $837,174 to $3,598,243.