Modeling retinal Alzheimer’s disease histopathology with human iPSC‐derived retinal organoids for mechanistic and DRUG DEVELOPMENT studies

The neuropathological features that characterize Alzheimer’s disease (AD), including the presence of beta‐amyloid (Aß) plaques and intracellular neurofibrillary tangles (NFTs) of abnormally phosphorylated Tau proteins (pTau), are manifested not only in the brain but also in the retina, an extension of the central nervous system. This is likely to contribute to the visual manifestations of AD that can pose additional challenges to this vulnerable population. Moreover, due to its accessibility and the availability of non‐invasive imaging technologies, the retina is being investigated as a potential biomarker of AD progression. In this context, hiPSC‐derived retinal organoids offer new opportunities for AD modeling that present advantages for DRUG DEVELOPMENT applications. Retinal organoids mimic the histoarchitecture of the native retina, have a consistent cellular composition, and are optically clear. Moreover, 3D automated reporter quantification (3D‐ARQ) technologies have been established to facilitate quantitative assay design in these models without loss of their 3D structure. Thus, we set out to develop and characterize an hiPSC‐derived retinal organoid model of AD that can be applied to the evaluation of pathophysiological mechanisms and to the validation of potential therapeutic drugs.