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Amyloid-β Disruption of Pericyte Control of Capillary Hemodynamics

淀粉样蛋白-β 破坏毛细血管血流动力学的周细胞控制

基本信息

批准号：
10658264
负责人：
Albert Louis Gonzales
金额：
$ 51.14万
依托单位：
UNIVERSITY OF NEVADA RENO
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-04-01 至 2028-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10658264
关键词：
Adult Affect Aging Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease pathology Alzheimer&apos s disease patient Amyloid beta-Protein Blood Blood Vessels Blood capillaries Blood flow Brain Cardiovascular Diseases Cardiovascular Pathology Cardiovascular system Cell Membrane Permeability Cells Cerebral Amyloid Angiopathy Cholesterol Data Daughter Dementia Deterioration Disease Electrophysiology (science)Endothelium Environment Erythrocytes Event Excision Failure Frequencies Functional disorder Genetically Engineered Mouse Health Image Impaired cognition Laser Scanning Microscopy Lead Lipid Bilayers Lipids Mediating Membrane Membrane Lipids Molecular Morphology Mus Muscle Cells Nerve Degeneration Neurodegenerative Disorders Neurons Nutrient Omega-3 Fatty Acids Optics Pathogenesis Pathology Perfusion Pericytes Permeability Phosphatidylinositol 4,5-Diphosphate Phosphatidylinositols Preparation Prevention Property Regional Blood Flow Resources Retina Role STIM1 gene Senile Plaques Sensory Signal Transduction Site Smooth Muscle Myocytes Stimulus Supporting Cell Techniques Testing Tissues Transgenic Mice Vascular Diseases Vascular Smooth Muscle Work abeta accumulation abeta oligomer aging brain arteriole cerebral capillary constriction hemodynamics in vivo in vivo evaluation insight mouse model neural neuron loss neuropathology neurovascular unit new therapeutic target novel pressure prevent sensor therapeutic target two-photon voltage wasting

项目摘要

PROJECT SUMMARY Alzheimer's Diseases—the most common cause of dementia in aging adults—is a slow, but progressive, deterioration of the brain that leads to neurodegeneration and cognitive impairment. The classic neuropathological sign of the disease is the accumulation of amyloid-β (Aβ)-containing plaques, which can lead to neuronal damage when free Aβ oligomers form Ca2+-permeable pores, causing membrane permeabilization and neuronal cell death. More recently, cardiovascular pathologies have been implicated in the progression of Alzheimer's Disease and other forms of dementia. However, how these pathologies contribute to the pathogenesis of Alzheimer's Disease is poorly understood; how vascular dysfunction potentiates the failure to clear toxic Aβ from ageing brains. Our recent work provides evidence that capillaries—the smallest vascular conduits and the point of nutrient delivery and waste removal blood and surrounding neurons—act as a sensory network that detects and responds to neural activity by promoting an increase in local blood flow. In addition, we observe that contractile ensheathing pericytes maintain the efficiency of network perfusion by controlling blood flow at capillary junctions. In Preliminary Results, we provide new evidence that Aβ peptide for Ca2+ permeable pores, leading to the increases of Ca2+ events in contractile pericytes, but not in nearby vascular smooth muscle cells. In addition, we show that Aβ peptide- mediated increases in the frequency of Ca2+ events lead to Ca2+ store depletion and inhibition of the voltage- gated Ca2+ channels. We propose to test our overarching hypothesis that Aβ leads to the progressive loss of pericyte function at capillary junctions leading to a reduction in capillary network perfusion efficiency, ultimately affecting the health and function of surrounding neurons. The aims of the current study are 1) To test the hypothesis that differences in membrane lipid environments enable free Aβ oligomers to form Ca2+-permeable pores in capillary pericytes; 2) To test the hypothesis that free Aβ oligomers deplete internal Ca2+ stores, leading to STIM1-mediated inhibition of voltage-gated Ca2+ channels; and 3) To elucidate the effects of Aβ oligomers on local and regional blood flow. Successful completion of these studies is expected to provide insights into how amyloid-β peptide accumulation disrupts blood flow within the microenvironment to negatively impact neuronal vitality and provide therapeutic targets for the prevention of the neurodegeneration that leads to cognitive impairment and dementia.

项目总结