Colocalization of Aluminum and Iron in Nuclei of Nerve Cells in Brains of Patients with Alzheimer’s Disease

Abstract

Increasing evidence indicates that metal-induced oxidative stress plays a pivotal role in the pathogenesis of Alzheimer’s disease (AD). Recently, the presence of 8-hydroxydeoxyguanosine, a biomarker of oxidative DNA damage, was demonstrated in nuclear DNA (nDNA) in the AD brain. Iron (Fe) is a pro-oxidant metal capable of generating hydroxyl radicals that can oxidize DNA, and aluminum (Al) has been reported to facilitate Fe-mediated oxidation. In the present study, we examined the elements contained in the nuclei of nerve cells in AD brains using scanning electron microscopy coupled with energy-dispersive X-ray spectroscopy (SEM-EDS). Our results demonstrated that Al and Fe were colocalized in the nuclei of nerve cells in the AD brain. Within the nuclei, the highest levels of both Al and Fe were measured in the nucleolus. The SEM-EDS analysis also revealed the colocalization of Al and Fe in the heterochromatin and euchromatin in neuronal nuclei in the AD brain. Notably, the levels of Al and Fe in the nucleus of nerve cells in the AD brain were markedly higher than those in age-matched control brains. We hypothesize that the colocalization of Al and Fe in the nucleus of nerve cells might induce oxidative damage to nDNA and concurrently inhibit the repair of oxidatively damaged nDNA. An imbalance caused by the increase in DNA damage and the decrease in DNA repair activities might lead to the accumulation of unrepaired damaged DNA, eventually causing neurodegeneration and the development of AD.

Sildenafil for the Treatment of Alzheimer’s Disease: A Systematic Review

“…Alzheimer's disease (AD) is the leading cause of dementia worldwide, and AD patients and their families urgently require novel therapeutics to prevent and slow the progression of this devastating disorder. Hallmarks of AD include amyloid-␤ (A␤) peptide secretion and deposition into neuritic plaques, tau protein hyperphosphorylation and neurofibrillary tangle formation, metal ion dyshomeostasis [1][2][3][4][5][6][7][8][9], oxidative stress and lipid, nucleic acid, and protein damage [10][11][12][13], abortive cell cycle reentry [14][15][16][17][18][19][20][21][22][23][24][25][26], neuroinflammation and microbial dysbiosis [27][28][29][30][31][32][33], insulin resistance [34,35], cerebrovascular dysfunction [36][37][38], synaptic dysfunction [39,40], neuronal loss, endoplasmic reticulum stress [41][42][43][44], and mitochondrial dysfunction [...…”

Quercetin-Conjugated Superparamagnetic Iron Oxide Nanoparticles Protect AlCl3-Induced Neurotoxicity in a Rat Model of Alzheimer’s Disease via Antioxidant Genes, APP Gene, and miRNA-101

“…Previously, it was reported that aluminum could increase the levels of reactive oxygen species in the brain tissue ( Bali et al, 2019 ; Simunkova et al, 2019 ). Based on the results obtained from ICP and higher concentrations of aluminum ions, this ion crosses BBB and enters the brain tissue, while in neurons, aluminum participates in the Fenton reaction in which iron is oxidized and induces oxidative stress ( Mujika et al, 2014 ; Yumoto et al, 2018 ). Currently, aluminum has been reported as an inducer of oxidative stress leading to the appearance of AD markers, so that it has been used to develop rat models of AD ( Almuhayawi et al, 2020 ; Ogunlade et al, 2020 ).…”

Nano-imaging trace elements at organelle levels in substantia nigra overexpressing α-synuclein to model Parkinson’s disease

“…The nucleolar compartment of nigral neurons, even in non-diseased conditions, displayed clear evidence for the abundant presence of P, S, Ca, but also of Zn and Fe. The presence of Fe in the nucleoli has so far been imaged by XRF in plants 47 and mammalian cells 48 , and by other techniques in aged or diseased brains 49 , 50 . Fe levels in nucleoli of dopaminergic neurons were quantified in the present work (see Table 1 ).…”