R01AG076940

Hippocampal Neurogenesis in Cognitive Function and Dysfunction in Alzheimer's Disease - Abstract

In contrast to rodents, little is known about neurogenesis in the human brain. The few studies that examined neurogenesis in the human hippocampus have come to vastly different conclusions. Determining the existence and course of hippocampal neurogenesis in the human brain is critical for the understanding of brain function, cognition, putative preventative and therapeutic approaches for the treatment of cognitive decline, Alzheimer's disease (AD), and related dementia (ADRD).

Our previous studies showed that hippocampal neurogenesis persists throughout the 10th decade of life. New neurons were observed in the brains of participants with no cognitive impairments (NCI), as well as in patients exhibiting mild cognitive impairments (MCI) or AD. Interestingly, the number of new neurons was significantly lower in MCI and AD compared to NCI. On the other hand, the number of early differentiating and mature astrocytes was increased in the AD brain. Importantly, higher numbers of neuroblasts were associated with better cognitive performance in the brains of aging, MCI, and AD patients. Intriguingly, levels of neurogenesis in the brains of superagers, individuals in their 80s who exhibit memory performance comparable to people in their 50s, were significantly greater compared to age-matched individuals with age-appropriate cognitive function.

Nevertheless, the observations above were made using the same neurogenic proxies used in the rodent brain, and the nature of cells in the human brain recognized by these proxies is not clear. Evidently, studies that could not detect neurogenesis in the human brain used the same proxies. Thus, the goal of this project is to test the hypothesis that hippocampal neurogenesis persists in the aged and AD human brain and its level is associated with cognitive function, by providing new evidence for the presence of hippocampal neurogenesis using novel tools that would validate previously used proxies.

Experiments in Aim 1 will examine the hypothesis that neural progenitor cells have a lower level of proliferation and preferable differentiation into astrocytes leading to fewer new neurons in MCI and AD, using multiplex RNA scope and neurogenic proxies. Experiments in Aim 2 will determine the spatial organization of hippocampal neurogenesis in NCI, MCI, and AD, and examine the hypothesis that autonomous and non-autonomous factors in the DG determine the level of human neurogenesis in the aging and AD brain, using a combination of spatial transcriptomics (PCISEQ) and RNAseq. Aim 3 will address whether new neurons play a role in cognitive reserve and resilience to AD. Experiments will examine the association between cognitive performance, hippocampal neurogenesis, and AD hallmarks in superagers, age-appropriate cognitive performance, MCI, and AD patients.

In summary, this project will provide novel crucial information about the presence of neurogenesis and its role in hippocampal function in the human aging and AD brain.

University Of Illinois

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]

Chicago, Illinois 60612 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 324% from $715,138 to $3,035,322.