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 ap...