R01AG082151

Atlas for Neuronal and Glial Cell Types Selectively Vulnerable to Proteinopathies during Progression of Alzheimer's Disease - Abstract

The long-term goal of this project is to elucidate multimodal mechanisms underlying selective vulnerability of neuronal and non-neuronal cells to proteinopathies during the progression of Alzheimer's disease (AD). The most notable feature of AD is its strikingly age- and sex-dependent regional onset and progression-selective vulnerability, which is manifest in distinct clinical presentations, e.g., memory impairment in AD and patterns of brain degeneration.

Recent studies on the staging of AD neuropathology showed AD-related tauopathy begins in the locus coeruleus (LC), followed by neurofibrillary tangles in the entorhinal cortex (EC), followed by hippocampal (HC), and then neocortex, e.g., prefrontal cortex (PFC). One hypothesis for selective vulnerability is that major AD risk genes are regionally restricted, but the results show they are rather broadly expressed.

A body of evidence supports that glia play multiple essential roles at different brain regions in AD pathogenesis. These data suggest that selective vulnerability is likely a result of interplay of intrinsic properties of neurons and glial cells in their response to proteinopathies in a dynamic and spatiotemporal manner at vulnerable brain regions. For example, EC neurons project multiple brain regions including the EC, PFC, and cerebellum. Yet, degeneration of EC and PFC occurs at different stages. In contrast, the cerebellum is largely not affected. There is emerging evidence that subpopulations of microglia treat excitatory and inhibitory neurons differently. Could different glial cell types or differential response to proteinopathies in different projecting sources and/or targets contribute to selective vulnerability?

These results underscore the central importance of understanding the diversity of cell types and molecular signature differences in both sexes at spatiotemporal, single-cell resolution and multimodal scales between vulnerable and less vulnerable neuronal and glial populations susceptible to proteinopathies in AD.

MAPTS305N;INT10+3 and APPNL-F knock-in (KI) AD mice displaying tau and ASS proteinopathies, respectively, will be used to achieve this goal. Preliminary results were obtained to support the project. First, barcoded single-neurons brain-wide projection mapping in controls demonstrates sex- and age-dependent differences in projections of LC neurons to selective targets. The results showed reciprocal innervations among these four brain regions. Second, the analysis of 16-month-old control and APPNL-F mice showed aberrant innervation patterns by norepinephrine (NE) neurons. Third, impaired prepulse inhibition (PPI) has been suggested to be a biomarker for prodromal AD. Importantly, PPI impairment was observed in the 5-month-old APPNL-F mice. Finally, single nuclei (SN)-RNAseq of the EC from 16-month-old control and APPNL-F mice showed selective loss of neuronal and non-neuronal cell types and differential expression of a list of genes, including those associated with neuronal and glial function and impaired PPI.

SN-transcriptomics and -epigenomics will be employed to identify vulnerable cell types followed by spatial transcriptomics to investigate spatiotemporal correlation between proteinopathies and vulnerable cell types and gene networks.

San Diego, California Salk Institute For Biological Studies

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]

La Jolla, California 92037 United States

Single Zip Code

Neuronal Vulnerability to Proteinopathies in Alzheimers Disease and Alzheimers Disease-Related Dementias (R01 Clinical Trial Not Allowed) (RFA-AG-23-028)

Amendment Since initial award the End Date has been extended from 02/29/28 to 02/28/29 and the total obligations have increased 100% from $2,790,703 to $5,580,121.