Metallobiology and therapeutic chelation of biometals (copper, zinc and iron) in Alzheimer’s disease: Limitations, and current and future perspectives

Fasae, Kehinde D.; Abolaji, Amos O.; Faloye, Tolulope R.; Odunsi, Atinuke Y.; Oyetayo, Bolaji O.; Enya, Joseph Igbo; Rotimi, Joshua A.; Akinyemi, Rufus; Whitworth, Alexander J.; Aschner, Michael

doi:10.1016/j.jtemb.2021.126779

Cited by 88 publications

(88 citation statements)

References 349 publications

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“…Based on the hypothesis that Fe accumulation is an important contributing factor in the pathogenesis of AD, therapeutic approaches to decrease Fe overload in AD by Fe chelation have been tried [330]. In an early small study of AD patients, Fe chelation with deferoxamine reduced the rate of decline of daily living skills [331]; however, this agent poorly crosses the BBB.…”

Section: Iron Accumulation and Pathology In Sporadic Neurodegenerativ...mentioning

confidence: 99%

Cerebral Iron Deposition in Neurodegeneration

et al. 2022

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Disruption of cerebral iron regulation appears to have a role in aging and in the pathogenesis of various neurodegenerative disorders. Possible unfavorable impacts of iron accumulation include reactive oxygen species generation, induction of ferroptosis, and acceleration of inflammatory changes. Whole-brain iron-sensitive magnetic resonance imaging (MRI) techniques allow the examination of macroscopic patterns of brain iron deposits in vivo, while modern analytical methods ex vivo enable the determination of metal-specific content inside individual cell-types, sometimes also within specific cellular compartments. The present review summarizes the whole brain, cellular, and subcellular patterns of iron accumulation in neurodegenerative diseases of genetic and sporadic origin. We also provide an update on mechanisms, biomarkers, and effects of brain iron accumulation in these disorders, focusing on recent publications. In Parkinson’s disease, Friedreich’s disease, and several disorders within the neurodegeneration with brain iron accumulation group, there is a focal siderosis, typically in regions with the most pronounced neuropathological changes. The second group of disorders including multiple sclerosis, Alzheimer’s disease, and amyotrophic lateral sclerosis shows iron accumulation in the globus pallidus, caudate, and putamen, and in specific cortical regions. Yet, other disorders such as aceruloplasminemia, neuroferritinopathy, or Wilson disease manifest with diffuse iron accumulation in the deep gray matter in a pattern comparable to or even more extensive than that observed during normal aging. On the microscopic level, brain iron deposits are present mostly in dystrophic microglia variably accompanied by iron-laden macrophages and in astrocytes, implicating a role of inflammatory changes and blood–brain barrier disturbance in iron accumulation. Options and potential benefits of iron reducing strategies in neurodegeneration are discussed. Future research investigating whether genetic predispositions play a role in brain Fe accumulation is necessary. If confirmed, the prevention of further brain Fe uptake in individuals at risk may be key for preventing neurodegenerative disorders.

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Section: Iron Accumulation and Pathology In Sporadic Neurodegenerativ...mentioning

confidence: 99%

Cerebral Iron Deposition in Neurodegeneration

et al. 2022

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“…15 Among all transition metal ions, iron (Fe), copper (Cu) and zinc (Zn) are widely recognized for their roles in pathogenesis and progression of the AD. 38 In this article, the discussion is emphasized on their 3 main aspects including i) effects on production and/or aggregation of the abnormal proteins (i.e., Aβ and tau) and their toxic forms (i.e., Aβ plaque and tau neurofibrillary tangles, NFTs), ii) effects on the reactive oxygen species (ROS) production and oxidative damages, and iii) effects on synaptic functions as summarized in Figure 3.…”

Section: Roles Of Transition Metal Ions In Admentioning

confidence: 99%

8-Hydroxyquinolines: A Promising Pharmacophore Potentially Developed as Disease-Modifying Agents for Neurodegenerative Diseases: A Review

Prachayasittikul,

Pingaew,

Prachayasittikul

et al. 2022

HETEROCYCLES

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8-Hydroxyquinoline (8HQ) is an attractive heterocyclic scaffold with well-known metal chelating property, broad-ranging pharmacological activities, and preferrable drug-likeness, thus, it had gained a continual attention in areas of drug development, especially, drug repurposing. Alzheimer's disease (AD) is one of globally health concern in an era of aging society and its management is considered challenging as effective disease-modifying drugs are still clinically unavailable. Loss of metal ion homeostasis is one of key factors contributing to pathogenesis and progression of AD in which its imbalance could trigger many related key factors and harmful events, especially, oxidative neuronal damages.Hence, restoration of homeostasis and distribution of brain's metal ions served to be a promising strategy for development of disease-modifying agents. In this review, essential key points relating to AD pathogenesis, roles of metal ions in AD, and pioneer 8HQ-based compounds are introduced. A series of recently reported 8HQbased neuroprotective compounds (i.e., derivatives, hybrids, conjugates, and metal complexes) focusing on compounds acting as metal chelators are reviewed. Related 8HQ-based neuroprotective compounds with other mechanisms of actions are also discussed. Additionally, summary of key contents is included to provide an 202

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“…The latter is produced through the sequential cleavage of amyloid precursor protein (APP) by β-secretase β-site APP cleavage enzyme 1, and the γ-secretase complex [105]. The full understanding of the pathogenesis of AD is still challenging and many hypotheses including neuroinflammation, oxidative stress, mitochondrial dysfunction, lipid metabolism, apoptosis, calcium and metal dyshomeostasis, and epigenetic changes have been proposed [106][107][108][109]. In addition, infectious agents have been found in the brain and postulated to be, through multiple mechanisms, involved in the pathogenesis of AD.…”

Section: The Pathogenic Role Of Gut Microbiota In Admentioning

confidence: 99%

The Endocannabinoid System: A Bridge between Alzheimer’s Disease and Gut Microbiota

Bisogno

Lauritano

Piscitelli

2021

Life

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Alzheimer’s disease (AD) is a neurodegenerative disease that progresses from mild cognitive impairment to severe dementia over time. The main clinical hallmarks of the disease (e.g., beta-amyloid plaques and neurofibrillary tangles) begin during preclinical AD when cognitive deficits are not yet apparent. Hence, a more profound understanding of AD pathogenesis is needed to develop new therapeutic strategies. In this context, the endocannabinoid (eCB) system and the gut microbiome are increasingly emerging as important players in maintaining the general homeostasis and the health status of the host. However, their interaction has come to light just recently with gut microbiota regulating the eCB tone at both receptor and enzyme levels in intestinal and adipose tissues. Importantly, eCB system and gut microbiome, have been suggested to play a role in AD in both animal and human studies. Therefore, the microbiome gut-brain axis and the eCB system are potential common denominators in the AD physiopathology. Hence, the aim of this review is to provide a general overview on the role of both the eCB system and the microbiome gut-brain axis in AD and to suggest possible mechanisms that underlie the potential interplay of these two systems.

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Metallobiology and therapeutic chelation of biometals (copper, zinc and iron) in Alzheimer’s disease: Limitations, and current and future perspectives

Cited by 88 publications

References 349 publications

Cerebral Iron Deposition in Neurodegeneration

Cerebral Iron Deposition in Neurodegeneration

8-Hydroxyquinolines: A Promising Pharmacophore Potentially Developed as Disease-Modifying Agents for Neurodegenerative Diseases: A Review

The Endocannabinoid System: A Bridge between Alzheimer’s Disease and Gut Microbiota

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