The link between Amyloid β and ferroptosis pathway in Alzheimer’s disease

ABSTRACT: Alzheimer’s disease (AD), currently affecting millions of people worldwide, is the most prevalent form of dementia. Treatment strategies aiming to interfere with the formation of amyloid β (Aβ) plaques and neurofibrillary tangles (NFTs), the two major AD hallmarks, have shown modest or no effect. Recent evidence suggests that ferroptosis, a type of programmed cell death caused by iron accumulation and lipid peroxidation, contributes to AD pathogenesis. Here we evaluate if Aβ is associated with ferroptosis pathways and whether ferroptosis inhibition could attenuate Aβ-related effects. The existing link between ferroptosis and AD has been largely based on cell culture and animal studies, while evidence from human brain tissue is limited. Performing positive pixel density scoring on immunohistochemically stained post mortem BA17 sections revealed that the progression of AD pathology was accompanied by decreased expression of nuclear receptor co-activator 4 (NCOA4) and glutathione peroxidase 4 (GPX4) in the grey matter (GM). The expression of ferroportin, NCOA4, GPX4, 4-hydroxy-2-nonenal (4HNE) and cytochrome C was significantly lower, while the expression of ferritin was higher in the Aβ plaque area compared to the immediate vicinity of the non-Aβ tissue in AD brain tissue. Taken together, these findings indicate a relationship between Aβ-related processes and the expression of ferroptosis-related proteins. Additionally, ferroptosis inhibition prevented Aβ pathology, decreased lipid peroxidation and restored iron storage in human AD iPSCs-derived brain cortical organoids (cBOs). Differential expression analysis of AD organoids compared to isogenic controls indicate activation of the ferroptotic pathway. This further supports the previously suggested link between Aβ-related pathology and ferroptosis. Determining the causality between development of Aβ plaques and deregulation of molecular pathways involved in ferroptosis is crucial for developing potential therapeutic interventions.

INSTRUMENT(S): Orbitrap Exploris 480

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Brain

DISEASE(S): Alzheimer's Disease

SUBMITTER: Justina Clarinda Wolters  

LAB HEAD: Justina Clarinda

PROVIDER: PXD047941 | Pride | 2025-05-06

REPOSITORIES: Pride