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Alzheimer's Disease Hallmark Pathology and Associated Inflammation in the Retina

阿尔茨海默病标志性病理学和视网膜相关炎症

基本信息

批准号：
10739484
负责人：
Maya Koronyo-Hamaoui
金额：
$ 88.01万
依托单位：
CEDARS-SINAI MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-04-01 至 2028-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10739484
关键词：
Adult Alzheimer disease screening Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease pathology Alzheimer&apos s disease patient Alzheimer’s disease biomarker Amyloid Amyloid beta-Protein Amyloidosis Autopsy Axon Blood Vessels Blood capillaries Blood-Retinal Barrier Brain Brain Pathology Cells Cerebral Amyloid Angiopathy Cerebrum Clinical Cognition Cognitive Cognitive deficits Color Data Data Analyses Data Science Data Set Dementia Deposition Development Diagnosis Disease Early Diagnosis Early identification Extravasation Future Gliosis Goals Grant Human Immunotherapy Individual Inflammation Inflammatory Lead Link Measures Metabolic Microglia Mitochondria Molecular Molecular Profiling Monitor Morbidity - disease rate Multiomic Data Mus Nerve Degeneration Neurodegenerative Disorders Neurofibrillary Tangles Non-Invasive Detection Pathogenesis Pathologic Pathologic Processes Pathology Pathway interactions Patients Pericytes Phenotype Photoreceptors Platelet-Derived Growth Factor beta Receptor Population Populations at Risk Positron-Emission Tomography Process Proteomics Research Resolution Retina Retinal Diseases Screening procedure Severities Site Spatial Distribution Synapses Tauopathies Tight Junctions Vascular Diseases Vision Visualization astrogliosis brain cell cell type cohort cranium diagnostic strategy effective intervention ganglion cell glial activation hippocampal atrophy in vivo inflammatory marker inflammatory milieu insight mild cognitive impairment mortality mouse model multimodal data neuropathology neurosensory neurovascular neurovascular unit new therapeutic target next generation novel novel diagnostics novel therapeutic intervention novel therapeutics optical imaging protein oligomer resilience response retinal imaging synaptic pruning tau Proteins tool transgenic model of alzheimer disease uptake validation studies vascular abnormality β-amyloid burden

项目摘要

PROJECT SUMMARY/ABSTRACT The central goal of this proposal is to investigate retinal microglial phenotypes as they relate to novel forms of tauopathy and amyloidosis in the Alzheimer's Disease (AD) retina and to determine their connections to retinal neurovascular unit alterations and synaptic loss as well as disease status in the brain. We will analyze postmortem retinas and paired brains from neuropathologically well-characterized patient donors with mild cognitive impairment (MCI), AD dementia, and normal cognition (NC), and resilient subjects who remained cognitively normal despite having AD pathology. Evidence of AD pathological hallmarks—amyloid β-protein (Aβ) plaques and neurofibrillary tangles (NFTs) composed of hyper-phosphorylated (p)tau protein—extending to the accessible retina is mounting, with parallels between retinal and brain pathology. Recently, we identified early and progressive deficiency in vascular platelet–derived growth factor receptor beta (vPDGFRβ) and pericyte loss in postmortem retinas of MCI and AD patients. Retinal vPDGFRβ was associated with retinal vAβ40 and vAβ42 loads, cerebral amyloid angiopathy severity, and cognitive scores. In old APPSWE/PS1ΔE9-transgenic (AD+) model mice, we revealed similarities between retinal and brain pathology and immunotherapy response. We also found that retinal capillary and vPDGFRβ losses link to vascular Aβ deposits in young and adult AD+ mice, and are associated with altered inner blood-retina barrier (iBRB) tight junctions and BRB leakage. In humans, our preliminary data suggest the existence of Aβ oligomers, diverse pTau and citrullinated Tau forms, microgliosis, astrogliosis, and cell-specific and synaptic losses in the retinas of MCI and AD patients, which correlate with brain Aβ, tauopathy, neurodegeneration, and cognitive status. Proteomics analysis identified novel molecular signatures of AD in the retina, with the largest overlap with a cortical region. Most significant pathways in the AD retina are related to inflammation, metabolic/mitochondrial damage, and neurodegeneration, especially in photoreceptors. Our initial findings also indicate increased neurodegeneration-associated microglia (MGnD) markers in the AD retina. In this project, retinal spatial distribution of AD hallmark pathology and associated inflammatory, neurovascular, and neurodegenerative markers will be determined and correlated with respective brain pathology and cognition. The specific objectives include 1) Characterize inflammatory processes and MGnD in relation to novel forms of tauopathy and amyloidosis in retinas of MCI and AD patients versus NC and resilient subjects; 2) Investigate synaptic and cell-type vulnerabilities and define their relations to tauopathy and microglial phenotypes in the same human cohort; and 3) Determine if iBRB damage is associated with vascular amyloidosis, tauopathy and inflammation in the human AD retina and in murine models. Computational data science tools will be applied to integrate the multi-omics data sets. Results will offer a deeper understanding of the molecular and cellular inflammatory, vascular, and neurodegeneration mechanisms of retinal and brain AD pathology, paving the path for novel therapeutic targets and next-generation retinal imaging diagnostic strategies.

项目总结/文摘