RF1NS139975

Vascular-immune mechanisms of cerebral amyloid angiopathy and Alzheimer's pathology - cognitive decline in the aging brain is driven by overlapping neurodegenerative and cerebrovascular pathologies.

Over 80% of Alzheimer's disease (AD) patients co-present with cerebral amyloid angiopathy (CAA), the vascular deposition of amyloid-β (Aβ).

Though CAA and parenchymal Aβ plaques intersect at the levels of Aβ generation and clearance—and share APOE4 as their strongest risk factor—they trigger distinct disease processes: CAA develops insidiously to erode vascular structure and function, induce microbleeds, foment neuroinflammation, and complicate anti-Aβ antibody therapies.

Thus, understanding the mechanisms of CAA formation, insult, and clearance in the context of Aβ plaque pathology and APOE genotype is essential to effectively target intertwined neurodegenerative and cerebrovascular pathways in dementia.

Yet, the molecular and cellular processes underlying CAA remain incompletely understood.

Single-cell genomics has provided insights into various neurological diseases—but not yet CAA because of a lack of high-quality human tissue at scale and the inability to effectively capture brain vascular cell types.

Further, animal models of AD have lacked the ability to precisely control CAA formation for its mechanistic study.

To address these challenges, we have assembled a multidisciplinary team with expertise spanning vascular neuropathology, clinical imaging, single-cell genomics of the neurovascular unit, AD models, microglia, and APOE biology.

We have organized 200 human postmortem brains along CAA progression from ROSMAP with rich demographic, genomic, pathologic, MRI imaging, and longitudinal cognitive data.

We will profile these samples with our new brain vascular and immune cell-capturing VINE-SEQ and spatial genomics approaches.

Further, we recently established in mouse models of AD a new paradigm where modulating microglial function is sufficient to control the timing and burden of CAA and microbleeds.

We hypothesize that in the healthy aging brain, microglia consolidate soluble Aβ into dense core parenchymal plaques to prevent more damaging vascular Aβ—and this process is disrupted by APOE4 and vascular dysfunction.

Thus, we expect enhancing or impairing microglial function will modulate the balance of CAA versus parenchymal Aβ plaque burden.

With parallel mechanistic studies in mouse models of CAA and molecular analyses of CAA in human tissue, we will elucidate key microglial mechanisms regulating the formation of vascular CAA versus parenchymal Aβ plaques, define single-cell and spatial human brain immunovascular signatures of CAA, and reveal how brain vascular Aβ clearance mechanisms synergize with microglia to clear CAA.

With hypothesis-driven functional studies and foundational human molecular datasets of CAA informing one another, our integrated studies will advance fundamental understanding of CAA to inform the development of sensitive blood biomarkers and new approaches to enhance the safety of anti-Aβ immunotherapies.

J.David Gladstone Institutes

(1) TO SUPPORT EXTRAMURAL RESEARCH FUNDED BY THE NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE (NINDS) INCLUDING: BASIC RESEARCH THAT EXPLORES THE FUNDAMENTAL STRUCTURE AND FUNCTION OF THE BRAIN AND THE NERVOUS SYSTEM, RESEARCH TO UNDERSTAND THE CAUSES AND ORIGINS OF PATHOLOGICAL CONDITIONS OF THE NERVOUS SYSTEM WITH THE GOAL OF PREVENTING THESE DISORDERS, RESEARCH ON THE NATURAL COURSE OF NEUROLOGICAL DISORDERS, IMPROVED METHODS OF DISEASE PREVENTION, NEW METHODS OF DIAGNOSIS AND TREATMENT, DRUG DEVELOPMENT, DEVELOPMENT OF NEURAL DEVICES, CLINICAL TRIALS, AND RESEARCH TRAINING IN BASIC, TRANSLATIONAL AND CLINICAL NEUROSCIENCE. THE INSTITUTE IS THE LARGEST FUNDER OF BASIC NEUROSCIENCE IN THE US AND SUPPORTS RESEARCH ON TOPICS INCLUDING BUT NOT LIMITED TO: DEVELOPMENT OF THE NERVOUS SYSTEM, INCLUDING NEUROGENESIS AND PROGENITOR CELL BIOLOGY, SIGNAL TRANSDUCTION IN DEVELOPMENT AND PLASTICITY, AND PROGRAMMED CELL DEATH, SYNAPSE FORMATION, FUNCTION, AND PLASTICITY, LEARNING AND MEMORY, CHANNELS, TRANSPORTERS, AND PUMPS, CIRCUIT FORMATION AND MODULATION, BEHAVIORAL AND COGNITIVE NEUROSCIENCE, SENSORIMOTOR LEARNING, INTEGRATION AND EXECUTIVE FUNCTION, NEUROENDOCRINE SYSTEMS, SLEEP AND CIRCADIAN RHYTHMS, AND SENSORY AND MOTOR SYSTEMS. IN ADDITION, THE INSTITUTE SUPPORTS BASIC, TRANSLATIONAL AND CLINICAL STUDIES ON A NUMBER OF DISORDERS OF THE NERVOUS SYSTEM INCLUDING (BUT NOT LIMITED TO): STROKE, TRAUMATIC INJURY TO THE BRAIN, SPINAL CORD AND PERIPHERAL NERVOUS SYSTEM, NEURODEGENERATIVE DISORDERS, MOVEMENT DISORDERS, BRAIN TUMORS, CONVULSIVE DISORDERS, INFECTIOUS DISORDERS OF THE BRAIN AND NERVOUS SYSTEM, IMMUNE DISORDERS OF THE BRAIN AND NERVOUS SYSTEM, INCLUDING MULTIPLE SCLEROSIS, DISORDERS RELATED TO SLEEP, AND PAIN. PROGRAMMATIC AREAS, WHICH ARE PRIMARILY SUPPORTED BY THE DIVISION OF NEUROSCIENCE, ARE ALSO SUPPORTED BY THE DIVISION OF EXTRAMURAL ACTIVITIES, THE DIVISION OF TRANSLATIONAL RESEARCH, THE DIVISION OF CLINICAL RESEARCH, THE OFFICE OF TRAINING AND WORKFORCE DEVELOPMENT, THE OFFICE OF PROGRAMS TO ENHANCE NEUROSCIENCE WORKFORCE DEVELOPMENT, AND THE OFFICE OF INTERNATIONAL ACTIVITIES. (2) TO EXPAND AND IMPROVE THE SMALL BUSINESS INNOVATION RESEARCH (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. TO UTILIZE THE SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM, TO STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND 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

93.866 - Aging Research

National Institute of Neurological Disorders and Stroke (NNDS) [HHS - NIH]

National Institute on Aging (NIA) [HHS - NIH]

San Francisco, California 941582261 United States

Single Zip Code

VCID Center Without Walls for Understanding and Leveraging Small Vessel Cerebrovascular Disease Mechanisms in ADRD (R01 - Clinical Trial Not Allowed) (RFA-NS-24-027)