Abstract
Iron dyshomeostasis is implicated in Alzheimer’s disease (AD) alongside β-amyloid and tau pathologies. Despite the recent discovery of ferroptosis, an iron-dependent form cell death, hitherto, in vivo evidence of ferroptosis in AD is lacking. The present study uniquely adopts an integrated multi-disciplinary approach, combining protein (Western blot) and elemental analysis (total reflection X-ray fluorescence) with metabolomics (1H nuclear magnetic resonance spectroscopy) to identify iron dyshomeostasis and ferroptosis, and possible novel interactions with metabolic dysfunction in age-matched male cognitively normal (CN) and AD post-mortem brain tissue (n = 7/group). Statistical analysis was used to compute differences between CN and AD, and to examine associations between proteins, elements and/or metabolites. Iron dyshomeostasis with elevated levels of ferritin, in the absence of increased elemental iron, was observed in AD. Moreover, AD was characterised by enhanced expression of the light-chain subunit of the cystine/glutamate transporter (xCT) and lipid peroxidation, reminiscent of ferroptosis, alongside an augmented excitatory glutamate to inhibitory GABA ratio. Protein, element and metabolite associations also greatly differed between CN and AD suggesting widespread metabolic dysregulation in AD. We demonstrate iron dyshomeostasis, upregulated xCT (impaired glutathione metabolism) and lipid peroxidation in AD, suggesting anti-ferroptotic therapies may be efficacious in AD.
Highlights
Prevailing evidence suggests iron dyshomeostasis as a contributing factor in Alzheimer’s disease (AD) pathogenesis, alongside amyloid plaques and tau tangles [1,2,3]
We demonstrate ferroptotic-like changes in the AD brain, with evidence of iron dyshomeostasis, increased expression of xCT and lipid peroxidation, co-existent with augmented excitatory glutamate: inhibitory GABA ratio
These combined metal/elemental, molecular and metabolic findings implicate oxidative stress and impaired glutathione antioxidation, concomitant with iron dyshomeostasis to be operant in AD (Fig. 12) and suggests therapies targeting ferroptosis are potentially beneficial
Summary
Prevailing evidence suggests iron (metal) dyshomeostasis as a contributing factor in Alzheimer’s disease (AD) pathogenesis, alongside amyloid plaques and tau tangles [1,2,3]. Iron dyshomeostasis has been proposed to be an additional factor in AD pathology as severe cognitive decline was shown to correlate with an elevated brain iron signal in amyloid-PET positive individuals [6]. The perturbed brain iron regulation in AD enables redox-active ferrous iron to both generate hydroxyl free radicals in the Fenton reaction and induce/enhance neuroinflammation, contributing to oxidative stress and neurodegeneration possibly via an irondependent cell death called ferroptosis [6,10,11,12,13]. During the process of ferroptosis, iron-induced lipid peroxidation causes catastrophic membrane rupture in conditions of diminished activity of a lipid repair enzyme, glutathione peroxidase 4 (GPX4) [14]. Inhibition of Xc- depletes glutathione levels and impairs GPX4 activity, thereby increases lipid peroxidation. Polyunsaturated fatty acids (PUFA) containing arachidonic acid are esterified with CoA by Acyl-CoA synthetase long chain family member 4 (ACSL4) forming phosphatidylethanolamines [15], which are vulnerable to peroxidation by iron-dependent lipoxygenases [16]
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