R01AG081931

Metabolic and Neural Activity Normalization by Cerebral Blood Flow Increase in AD/ADRD Models - Summary

Although many biomarkers have been identified in AD/ADRD, the most important effect is cognitive function. Links between AD/ADRD symptoms and cerebral blood flow deficits or vascular risk factors such as hypertension are well recognized in patients, but the mechanisms are still under investigation.

In mouse models of AD, about 2% of capillaries are occluded by an arrested neutrophil, and these stalled capillaries have a profound effect on cerebral blood flow. Such capillary stall perfusion deficits (CSPD) could reduce oxygenation and nutrient delivery to neurons and are therefore potential drivers of cognitive dysfunction in AD/ADRD.

In AD mouse models, working memory performance is rescued within hours of reducing the incidence of stalled capillaries to increase cerebral blood flow using antibodies against the neutrophil protein LY6G. CSPD has also been observed in a new non-amyloid ADRD model, hypertensive mice with targeted replacement of the murine ApoE gene with the AD-promoting ApoE4 human allele. In this mouse, rapid rescue of behavior and flow are observed after treatment with the platelet inhibitor prasugrel, suggesting a different cellular cause of CSPD than that observed in the AD models.

The rapid time scales of cognitive recovery are too fast for many pathological processes and rule out vascular or neural remodeling. Instead, the speed of memory improvement suggests that changes in the dynamic firing pattern of neurons underlie the rescue and that improved metabolic support by increased cerebral blood flow is a critical factor in determining the functionality of neural circuits. This suggests that slower processes such as protein accumulation and remodeling can be secondary to fast effects linked to improvement of oxygen and metabolite delivery after blood flow increase.

This proposal tests the idea that cerebral blood flow recovery leads to corrections in blood oxygenation and in oxygen usage, which then result in metabolic and cellular functional recovery in neurons (Aim 1). Such metabolic changes are hypothesized to underlie corrections of aberrant neural activity that ultimately determine behavior. Aim 1 will use gamma oscillations, coordinated neural activity associated with healthy cortical function, as a simultaneous measure of the consequence of the oxygenation changes.

In AD mouse models, an imbalance in the activity of inhibitory and excitatory neurons results in reduced fidelity of neural encoding of stimuli. Aim 2 asks if the blood flow improvement also corrects this activity imbalance and improves the precision of stimulus encoding for orientation-tuned neurons in the visual cortex.

Aim 3 tests for normalization of activity in hippocampal circuits involved in the formation and consolidation of memory, directly testing the neural circuits involved in the memory tasks that CSPD reduction improves performance in. Age and sex dependence of these phenomena are investigated in the APP/PS1 model of AD, and this study also compares to a new ApoE4-hypertension model and wild-type animals with bead injections to mimic capillary stalls.

Understanding the mechanism of the rapid improvement in memory function after eliminating CSPD could lead to future therapies that modulate the cognitive symptoms in AD/ADRD.

Cornell University

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]

Ithaca, New York 148537202 United States

Single Zip Code

Mechanisms of Brain Hypoperfusion in AD/ADRD (R01 Clinical Trial Not Allowed) (RFA-AG-23-014)

Amendment Since initial award the total obligations have increased 190% from $1,170,347 to $3,391,148.