Background: Alzheimer's disease (AD) and age-related macular degeneration (AMD) present
similarities, particularly with respect to oxidative stress, including production of 4-Hydroxy-2-
nonenal (HNE). AMD has been named the AD in the eye. The Müller cells (MC) function as a principal
glia of the retina and maintain water/potassium, glutamate homeostasis and redox status. Any MC dysfunction
results in retinal neurodegeneration.
Objectives: We investigated the effects of HNE in human MC.
Results: HNE induced an increase of the reactive oxygen species associated with mitochondrial dysfunction
and apoptosis. HNE induced endoplasmic reticulum (ER) stress (upregulation of GRP78/Bip,
and the proapoptotic factor, CHOP). HNE also impaired expression of genes controlling potassium homeostasis
(KCNJ10), glutamate detoxification (GS), and the visual cycle (RLBP1). MC adaptive response
to HNE included upregulation of amyloid-β protein precursor (AβPP). To determine the role of
AβPP, we overexpressed AβPP in MC. Overexpression of AβPP induced strong antioxidant and anti-ER
stress (PERK downregulation and GADD34 upregulation) responses accompanied by activation of the
prosurvival branch of the unfolded protein response. It was also associated with upregulation of major
genes involved in MC-controlled retinal homeostasis (KCNJ10, GS, and RLBP1) and protection against
HNE-induced apoptosis. Therefore, AβPP is an ER and oxidative stress responsive molecule, and is able
to stimulate the transcription of major genes involved in MC functions impaired by HNE.
Conclusion: Our study suggests that targeting oxidative and ER stress might be a potential therapeutic
strategy against glia impairment in AMD and AD, in light of the common features between the two pathologies.