RF1AG082314

Microglial Regulation of Neuronal Activity in TDP-43 Neurodegeneration - Project Summary

Microglia, as the resident immune cells of the central nervous system, are key players in aging and neurodegenerative diseases, such as Alzheimer's disease (AD) and AD-related dementias (ADRD). However, how microglia sense and regulate neurodegeneration remains largely unknown.

TDP-43 is a DNA-binding protein that is a main component of the protein aggregates found in amyotrophic lateral sclerosis (ALS), frontotemporal lobar dementia (FTLD), and AD. In this study, we utilized an inducible mouse model of TDP-43 translocation (RNLS8) that can mimic characteristic features of TDP-43 related neurodegeneration.

Using in vivo two-photon imaging, we have demonstrated that RNLS8 mice show neuronal hyperactivity in the cortex during disease progression, which is associated with unique rod-shaped microglia aligning along neuronal dendrites in the layer 4 cortex.

Based on these exciting observations, we hypothesize that microglia have neuroprotective roles by regulating cortical microcircuits and attenuating neuronal hyperactivity in response to TDP-43 related neurodegeneration. We will test this hypothesis with the following three aims:

Aim 1: Determine the functional heterogeneity of microglial activation in TDP-43 neurodegeneration. We will use chronic, in vivo two-photon imaging to determine the spatiotemporal activation of microglia, including process dynamics, landscape changes, and proliferation. In addition, we will examine microglial Ca2+ activity using a newly developed microglial GCAMP7S mouse line and TREM2 dependence. The results from this aim will uncover microglial heterogeneity in different phases of TDP-43 related neurodegeneration.

Aim 2: Investigate how microglia regulate cortical microcircuits in TDP-43 neurodegeneration. We will study microglia-neuron interactions in different cortical layers during disease progression and recovery in RNLS8 mice using simultaneous two-photon and electron microscopy. We will also determine how microglial TREM2 regulates neuronal circuits, particularly during the early phases of disease progress, in TDP-43 related neurodegeneration.

Aim 3: Manipulate microglia as a potential therapeutic target in TDP-43 neurodegeneration. We will precisely control microglial function using chemogenetics in the different phases of disease and delineate microglial contributions. In addition, we will target TREM2 for treatment of TDP-43 related neurodegeneration.

Our group is perfectly poised to exploit novel methods of imaging microglia-neuron interactions and study their precise function in aging and TDP-43 related neurodegeneration like ALS, FTLD, and AD. These innovative approaches will provide transformative insights into microglial mechanisms of regulating TDP-43 related neurodegeneration and spawn putative therapeutic targets that will ultimately help patients with ALS, FTLD, AD, and ADRD.

University Of Texas Health Science Center At Houston

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]

Houston, Texas 77030 United States

Single Zip Code

Change of Recipient Organization (Type 7 Parent Clinical Trial Optional) (PA-21-268)

Amendment Since initial award the total obligations have decreased 12% from $2,188,217 to $1,931,983.