R01AG071697

Neuronal ApoE Drives Selective Neurodegeneration in Alzheimer's Disease - Project Summary

Selective neurodegeneration is a critical causal factor in Alzheimer's disease (AD); however, the mechanisms that lead some neurons to perish while others remain resilient are unknown. There is regional susceptibility to AD-related neurodegeneration in the hippocampus and entorhinal cortex. Even within vulnerable neuronal populations, however, some cells are lost early while others prove more resilient.

With recent technical improvements in single-cell analysis, we are able for the first time to examine the variability that drives regional and cellular differences in susceptibility to neurodegeneration. The major genetic risk factor for Alzheimer's disease is apolipoprotein E4 (ApoE4), which increases disease risk and decreases age of onset in carriers. Within the central nervous system, ApoE is produced primarily in astrocytes but also in neurons following stress, injury, and aging. Neuronal ApoE4 expression diminishes synaptic plasticity, impairs synaptogenesis, and decreases synaptic density both in vitro and in vivo.

This proposal is based on intriguing preliminary studies. (1) Single-nucleus RNA-sequencing data from our lab have revealed a link between neuronal ApoE and neuronal expression of the major histocompatibility complex class I (MHC-I). Like ApoE, MHC-I is expressed in neurons following stress, injury, and aging. Neuronal MHC-I is localized to post-synaptic densities, where they limit long-term potentiation, enhance long-term depression, and mediate synaptic pruning during development and, potentially, in neurodegenerative diseases. Our discovery of neuronal ApoE upregulation of MHC-I provides insight into the mechanism by which both proteins potentially work in concert to contribute to synapse loss and eventually to selective neurodegeneration.

(2) In AD patients, neuronal ApoE expression correlates with neuronal MHC-I expression, which in turn predicts severity of tau pathologies. (3) In AD model mice or cultured primary neurons, neuron-specific ApoE4 knockout decreases neuronal MHC-I expression and rescues neuronal and synaptic loss, establishing a causal relationship between neuronal ApoE, upregulation of MHC-I, and selective neurodegeneration in AD.

To capitalize on these novel findings and recent technical improvements in single-cell analyses, this proposal aims to determine the ApoE-expression-high and MHC-I-expression-high neuron populations and explore their relationships with selective neurodegeneration across AD-susceptible and AD-resistant brain regions of ApoE-KI mice with different ApoE genotypes at different ages (Aim 1). We will also determine how ApoE is regulating neuronal expression of MHC-I and how this expression leads to Alzheimer's disease-related pathologies (Aim 2). Finally, we propose to determine the extent to which this ApoE and MHC-I-mediated neuronal loss is caused by signaling to microglia (Aim 3), which has been heavily implicated in Alzheimer's disease pathogenesis.

The outcome of the proposed studies should shed light on the mechanisms underlying regional, cell-type-specific, and within-cell-type selective vulnerability to Alzheimer's disease.

J.David Gladstone Institutes

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]

San Francisco, California 941582261 United States

Single Zip Code

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)

Amendment Since initial award the total obligations have increased 398% from $817,317 to $4,070,240.