R01AG080842

Role of LRP1 in Alzheimer's Disease - Alzheimer’s disease (AD) is a serious public health problem. AD is the most common cause of dementia, which is pathologically characterized by the accumulation of amyloid plaques and tau-containing neurofibrillary tangles in the brain.

AD is clinically manifested as progressive memory loss and cognitive impairment, leading to prolonged disability and eventual death. Yet, the cellular mechanisms underlying AD pathogenesis are not fully understood and no effective therapy is currently available for AD.

Our preliminary data point to the important role of low-density lipoprotein receptor-related protein 1 (LRP1) in the choroid plexus (CHP) and tancytes that is significant in the optimal regulation of amyloid-beta (A) and tau efflux. We found that deletion of LRP1 in the CHP leads to a significant decrease in A clearance from the cerebrospinal fluid (CSF) into circulation.

Interestingly, we also found that LRP1 in tancytes is necessary to regulate tau clearance from the CSF to the blood. Importantly, LRP1 physically binds to leptin receptor (LEPR) in response to A or tau. Furthermore, we observed that diet-induced overnutrition impairs A clearance from the brain and obesity-related metabolic parameters negatively correlate with short-term memory.

We therefore hypothesize that LRP1 in the CHP and tancytes is essential for regulating A and tau clearance, which is coupled with the LEPR to exert transcytosis of these proteins from the CSF to circulation. Thus, an impaired LRP1 action causes A and tau accumulation in the brain, leading to AD. Obesity further aggravates LRP1-dependent A and tau efflux, accelerating cognitive decline.

To this end, we will (i) establish the role of LRP1 in controlling A efflux in the choroid plexus; (ii) explore the significance of LRP1 in regulating tau transport in tancytes. To accomplish these goals, we will employ state-of-the-art biochemical, molecular, cellular, and metabolic physiological techniques, including genetically engineered tissue-specific transgenic mouse models, in vivo live two-photon imaging, and Cre-inducible AAV system.

These studies will provide a unique opportunity to establish a novel mechanism implicating LRP1 as a key determinant of A and tau efflux. The data generated from these timely studies may offer new insights into the underlying mechanisms of LRP1-dependent A and tau clearance in the etiopathogenesis of AD and provide new therapeutic targets for AD and related dementia.

Beth Israel Deaconess Medical Center

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]

Boston, Massachusetts 022155400 United States

Single Zip Code

Research on Current Topics in Alzheimer's Disease and Its Related Dementias (R01 Clinical Trial Optional) (PAR-22-093)

Amendment Since initial award the total obligations have increased 281% from $867,804 to $3,306,426.