U01AG076804

Mapping Cellular Resolution Connectopathies in Aging and Alzheimer's Disease - Project Summary/Abstract

The proposed project, "Mapping Cellular Resolution Connectopathies in Aging and Alzheimer's Disease," will systematically and comprehensively characterize cell-type specific anatomical and molecular phenotypes across aging and Alzheimer's disease (AD) in the entorhinal cortex (ENT): the ground zero of AD pathology.

We will map cellular resolution, age-dependent morpho-molecular phenotypes of ENT projection neurons by performing single-nucleus RNA-sequencing and methylomic analysis in 2M, 9M, and 18M APPSAA-(KI/KI) male and female mice. Novel genetic sparse labeling will be used to label and characterize the morphology of ENT pyramidal neurons in different cortical layers in APPSAA-(KI/KI)/MORF3/CUX2-CREER and APPSAA-(KI/KI)/MORF3/ETV1-CREER mice.

These studies will provide comprehensive data on how molecularly defined ENT neuronal cell types interact with age, sex, and AD pathology to confer progressive transcriptomic/epigenomic, morphological, and synaptic deficits in vivo. In addition, we will map the age-dependent morpho-molecular phenotypes of ENT projection neurons in humanized tau models, MAPT(H1)-GR*N279K and their MAPT(H1) controls.

A combined single-nucleus transcriptomics and genome-wide chromatin accessibility assays will be applied to MAPT(H1)-GR*N279K and MAPT(H1) male and female mice at 2M, 9M, and 18M to define integrated transcriptomic/epigenomic ENT neuronal cell types and to identify neuronal subsets undergoing age-dependent multi-modal molecular dysregulation in mutant "humanized" tau mouse models.

RNAscope multiplex in situ hybridization and GeoMx digital spatial profiling analyses will be performed to identify morpho-molecular types of neurons in ENT that are most affected in MAPT(H1)-GR*N279K knock-in mice compared to MAPT(H1) mice during aging.

To identify age-related connectional vulnerabilities and to map connectivity disruptions in AD, we will systematically quantify changes of axonal outputs arising from genetically and connectionally defined ENT cell types using 2M, 9M, and 18M male and female CUX2-CREER and ETV1-CREER mice. Cell-type specific connectivity disruptions will also be examined in two next-generation AD mouse models, APP knock-in (APPSAA-KI/KI with wildtype controls) and MAPT(H1)-GR*N279K (with MAPT(H1) controls), across ages and in both sexes.

Novel viral sparse labeling will be used to characterize age- and AD-related axonal dystrophy, while genetic sparse labeling in newly generated MORF3 mouse lines will help to identify local morphological changes in ENT cell types. Age- and AD-related morphological compromises to ENT input neurons will be studied along with their synaptic disruptions onto different ENT cell types.

Finally, we will establish a cloud-based visualization platform to map the integrated molecular-anatomic circuit deficits of aging and AD to the Allen Common Coordinate Framework to facilitate dissemination and analysis of the data. Although the focus of the current project is the ENT, the pipelines established for data production, collection, and analysis can be scaled up to identify brainwide cell-type specific anatomic-molecular deficits in aging and other late-onset AD mouse models.

Los Angeles University Of California

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]

Los Angeles, California 900958347 United States

Single Zip Code

The Cellular Scale Connectome in Aging and Alzheimers Disease (U01 Clinical Trial Not Allowed) (RFA-AG-22-008)

Amendment Since initial award the total obligations have increased 300% from $2,874,982 to $11,497,463.