Human iPSC-derived retinal organoids develop robust Alzheimer's disease neuropathology

Area of Science:

• Neuroscience
• Stem Cell Biology
• Ophthalmology

Background:

• Alzheimer's disease (AD) affects millions globally, characterized by brain amyloid beta (Aβ) plaques and tau tangles.
• Recent findings indicate AD pathology is also present in the retina, suggesting its potential as a biomarker for early diagnosis.
• Developing effective treatments for AD remains a critical unmet need.

Purpose of the Study:

• To create and characterize a novel human retinal organoid (RO) model from familial AD patients with APP gene mutations.
• To evaluate the cellular composition and presence of AD histopathological hallmarks (Aβ and pTau) in these AD-ROs.
• To establish a proof-of-concept assay for quantifying amyloid levels in retinal organoids.

Main Methods:

• Generation of human retinal organoids from induced pluripotent stem cells (iPSCs) of familial AD patients and healthy controls.
• Immunofluorescence and histological staining to assess cellular makeup and AD pathology.
• Development of an assay for quantifying amyloid levels in whole organoids.

Main Results:

• AD-ROs exhibit similar cellular composition to control ROs but show elevated levels of Aβ and phosphorylated Tau (pTau).
• The study successfully demonstrated an assay for measuring amyloid levels within the organoids.
• The developed model accurately recapitulates key AD histopathological features in a retinal context.

Conclusions:

• The novel human AD retinal organoid model serves as a valuable in vitro tool for studying AD pathophysiology.
• This model facilitates drug screening and biomarker discovery for early AD detection and therapeutic development.
• Retinal organoids offer a promising avenue for non-invasive AD diagnostics and research.