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

> **NIH NIH R01** · CEDARS-SINAI MEDICAL CENTER · 2024 · $824,043

## Abstract

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...

## Key facts

- **NIH application ID:** 10930883
- **Project number:** 5R01AG055865-07
- **Recipient organization:** CEDARS-SINAI MEDICAL CENTER
- **Principal Investigator:** Maya Koronyo-Hamaoui
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $824,043
- **Award type:** 5
- **Project period:** 2018-04-01 → 2028-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10930883

## Citation

> US National Institutes of Health, RePORTER application 10930883, Alzheimer's Disease Hallmark Pathology and Associated Inflammation in the Retina (5R01AG055865-07). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10930883. Licensed CC0.

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