R01AG077611

Neural Circuit Disruption in Freely-Behaving Models of Alzheimer's Disease - Background Summary/Abstract

Determining how A and tau degrade neural systems function in Alzheimer's disease remains an essential objective. Although much has been learned from models of early onset Alzheimer's disease (EOAD), including demonstration of aberrant neuronal activity and calcium overload in anesthetized amyloid models, the generalizability of these observations depends on two major caveats: first, it is not clear how findings under anesthesia extrapolate, particularly as the effects of amyloid and tau appear to depend on behavioral state. Second, it is not clear whether findings in EOAD models will inform understanding of late onset Alzheimer's disease (LOAD), which is far more common and arises in association with multiple genetic risk factors.

To address these issues, we will apply and integrate a series of new technologies. To extend studies to freely behaving animals and determine the behavioral state-dependence of A's impact on neuronal physiology, we will employ the Inscopix mini-microscope to monitor calcium activity together with concomitant multi-electrode recordings to assess brain oscillations.

To extend studies to LOAD, we study and contrast the APP/PS1 model of EOAD with the new HABETA.APOE4.TREM2*R47H model of LOAD. This model, which includes knock-in of the humanized APP gene in concert with the strong risk variants APOE (humanized APOE4) and TREM2*R47H, develops elevated levels of A42 and A40.

To evaluate tau's contribution to neuronal dysfunction and its interactions with A in these amyloid models, we employ an AAV vector that expresses equimolar levels of human tau and GCAMP6F, enabling dynamic calcium imaging in tau-laden cells with the mini-microscope.

To evaluate how the development of tau aggregates interacts with amyloid to affect neuronal physiology, we combine mini-microscope imaging of dynamic calcium activity with 2-photon imaging of tangles and plaques.

We hypothesize that in both APP/PS1 (to model EOAD) and HABETA.APOE4.TREM2*R47H (to model LOAD), A and tau will be associated with behavioral state-dependent changes in neuronal activity, brain oscillations, and calcium overload; that tau's state-dependent effects will dominate those of A in the EOAD and LOAD models; and that the development of tau aggregates will synergistically interact with amyloid to degrade neuronal activity.

Together, these efforts will establish how A and tau impair neural systems function, advancing Alzheimer's disease modeling and informing therapeutic development.

The General Hospital Corporation

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]

Charlestown, Massachusetts 02129 United States

Single Zip Code

Research on Current Topics in Alzheimer's Disease and Its Related Dementias (R01 Clinical Trial Optional) (PAR-19-070)

Amendment Since initial award the total obligations have increased 299% from $765,473 to $3,056,597.