Astrocyte activation and protein aggregation in the retina of Alzheimer's disease patients

Abstract

AbstractAlzheimer's disease (AD), a primary cause of dementia in the aging population, is characterized by intracellular and extracellular aggregates of misfolded proteins, as amyloid‐beta plaques and tau tangles, together with neurodegeneration and glial activation in the brain. It is commonly thought that the lack of early diagnostic criteria is among the main causes of pharmacological therapy and clinical trials failure; therefore, the actual challenge is to define new biomarkers and non‐invasive technologies to measure neuropathological changes in vivo at pre‐symptomatic stages. Recent evidences obtained from human samples and mouse models indicate the possibility to detect protein aggregates and other pathological features in the retina, paving the road for non‐invasive rapid detection of AD biomarkers. Here, we report the presence of amyloid beta plaques, tau tangles, neurodegeneration and detrimental astrocyte and microglia activation according to a disease associated microglia phenotype (DAM). Thus, we propose the human retina as a useful site for the detection of cellular and molecular changes associated with Alzheimer's disease.We also developed novel 2D and 3D in vitro models of AD related retinal tauopathy, obtaining derived retinal cultures from iPSC harbouring an intronic tau mutation. We report here that mutated tau induces not only tau hyperphosphorylation, but also impaired retinogenesis and altered astrocytic development.