Cellular Senescence and Iron Dyshomeostasis in Alzheimer's Disease

Abstract

Iron dyshomeostasis is a feature of Alzheimer's disease (AD). The impact of iron on AD is attributed to its interactions with the central proteins of AD pathology (amyloid precursor protein and tau) and/or through the iron-mediated generation of prooxidant molecules (e.g., hydroxyl radicals). However, the source of iron accumulation in pathologically relevant regions of the brain and its contribution to AD remains unclear. One likely contributor to iron accumulation is the age-associated increase in tissue-resident senescent cells that drive inflammation and contribute to various pathologies associated with advanced age. Iron accumulation predisposes ageing tissue to oxidative stress that can lead to cellular dysfunction and to iron-dependent cell death modalities (e.g., ferroptosis). Further, elevated brain iron is associated with the progression of AD and cognitive decline. Elevated brain iron presents a feature of AD that may be modified pharmacologically to mitigate the effects of age/senescence-associated iron dyshomeostasis and improve disease outcome.

Keywords: Alzheimer’s disease; chelators; ferroptosis; iron homeostasis; senescence.

Figure 1

Cellular senescence is a potential contributor to the age-associated accumulation of brain iron. Factors that influence brain iron with age include inflammation, altered vasculature, and altered metabolism. Elevated brain iron is associated with Alzheimer’s disease (AD) pathology, cognitive decline, and may lead to neuron loss via iron-dependent oxidative cell death such as ferroptosis. Iron chelation may mitigate some of these effects and alleviate AD progression.