metal dyshomeostasis and Alzheimer's

Neurological disorders (NDs) have a negative impact on the lives of individuals. There could be two explanations for this: unclear aetiology and lack of effective therapy. However, research in the past few years has revealed the role of bio-metals dyshomeostasis in NDs. The imbalance in copper (Cu) concentration may be one of the main causative factors in NDs. In this review, we have discussed the role of Cu in NDs, especially Alzheimer's disease (AD), including the molecular mechanisms involved in Cu-associated NDs like oxidative stress, neuroinflammation, and protein misfolding...

Alzheimer's disease (AD) is the most common cause of dementia, which arises due to low levels of acetyl and butyrylcholines, an increase in oxidative stress, inflammation, metal dyshomeostasis, Aβ and tau aggregations. The currently available drugs for AD treatment can provide only symptomatic relief without interfering with pathological hallmarks of the disease. In our ongoing efforts to develop naturally inspired novel multifunctional molecules for AD, systematic SAR studies on EJMC-4e were caried out to improve its multifunctional properties...

Ferroptosis is a vital driver of pathophysiological consequences of Alzheimer's disease (AD). High-efficiency pharmacological inhibition of ferroptosis requires comprehensive coordination of diverse abnormal intracellular events, which is an urgent problem and great challenge for its application in AD treatment. Herein, a triphenylphosphonium-modified quercetin-derived smart nanomedicine (TQCN) is developed for multipronged anti-ferroptosis therapy in AD. Taking advantage of the favorable brain-targeting and mitochondria-locating properties, TQCN can efficiently chelate iron through phytopolyphenol-mediated spontaneous coordination and self-assemble into metal-phenolic nanocomplexes in situ , exerting escalating exogenous offensive effects to attenuate iron overload and its induced free radical burst...

The pathogenesis of Alzheimer's disease (AD) is complex. So far there is no effective drug to treat the disease. The pathological changes of AD began 30 years before symptoms, so early diagnosis is considered to be important for AD treatment. Integrating diagnosis and therapy into a single regent has provided a new opportunity for AD treatment. Given that metal dyshomeostasis is thought to be one of the key factors to cause AD, a Schiff base substituted coumarin (probe 1) has been designed and synthesized as a selective metal chelator for multi-factor anti-AD in this work...

Neurodegenerative diseases affect millions of people worldwide. The failure of the enzymatic degradation, the oxidative stress, the dyshomeostasis of metal ions, among many other biochemical events, might trigger the pathological route, but the onset of these pathologies is unknown. Multi-target and multifunctional molecules could address several biomolecular issues of the pathologies. The tripeptide GHK, a bioactive fragment of several proteins, and the related copper(II) complex have been largely used for many purposes, from cosmetic to therapeutic applications...

Numerous neurological disorders, including prion, Parkinson's, and Alzheimer's disease (AD), are identified as being caused by alterations in protein conformation, aggregation, and metal ion dyshomeostasis. Recent years have seen a significant increase in the exploration and study of natural products (NPs) from plant and microbial sources for their therapeutic potential against several diseases, including cancer, diabetes, cardiovascular disease, and neurodegenerative diseases. In this study, we have examined the effect of two NPs, cycloastragenol (CAG) and punicalagin (PCG), on the metal-induced oligomerization and aggregation of Aβ25 - 35 and PrP106 - 126 peptides...

Alzheimer's disease (AD) is a progressive age-related neurodegenerative brain disorder, which leads to loss of memory and other cognitive dysfunction. The underlying mechanisms of AD pathogenesis are very complex and still not fully explored. Cholinergic neuronal loss, accumulation of amyloid plaque, metal ions dyshomeostasis, tau hyperphosphorylation, oxidative stress, neuroinflammation, and mitochondrial dysfunction are major hallmarks of AD. The current treatment options for AD are acetylcholinesterase inhibitors (donepezil, rivastigmine, and galantamine) and NMDA receptor antagonists (memantine)...

The calcium-binding protein S100A9 is recognized as an important component of the brain neuroinflammatory response to the onset and development of neurodegenerative disease. S100A9 is intrinsically amyloidogenic and in vivo co-aggregates with amyloid-β peptide and α-synuclein in Alzheimer's and Parkinson's diseases, respectively. It is widely accepted that calcium dyshomeostasis plays an important role in the onset and development of these diseases, and studies have shown that elevated levels of calcium limit the potential for S100A9 to adopt a fibrillar structure...

Down syndrome (DS), which is caused by triplication of human chromosome 21 (Hsa21), exhibits some physical signs of accelerated aging, such as graying hair, wrinkles and menopause at an unusually young age. Development of early-onset Alzheimer's disease, which is frequently observed in adults with DS, is also suggested to occur due to accelerated aging of the brain. Several Hsa21 genes are suggested to be responsible for the accelerated aging in DS. In this review, we summarize these candidate genes and possible molecular mechanisms, and discuss the related key factors...

Copper performs an important role in the brain, but in high levels it can be neurotoxic. Further, some authors have described that copper dyshomeostasis could be related with neurodegenerative diseases. Thus, this review was performed to observe whether high copper levels are related to Alzheimer's and Parkinson's diseases (AD and PD), using the literature published recently. Articles that measured copper levels in AD or PD patients was included, as well as they that measured copper levels in models used to mimic these diseases...

Metal ions are fundamental to guarantee the regular physiological activity of the human organism. Similarly, vitamins play a key role in many biological functions of the metabolism, among which are coenzymes, redox mediators, and antioxidants. Due to their importance in the human organism, both metals and vitamins have been extensively studied for their involvement in neurodegenerative diseases (NDs). However, the full potential of the interaction between vitamins and metal ions has not been fully explored by researchers yet, and further investigation on this topic is needed...

Trace elements such as iron (Fe), zinc (Zn), copper (Cu), and manganese (Mn) are absorbed from food via the gastrointestinal tract, transported into the brain, and play central roles in normal brain functions. An excess of these trace elements often produces reactive oxygen species and damages the brain. Moreover, increasing evidence suggests that the dyshomeostasis of these metals is involved in the pathogenesis of neurodegenerative diseases, including Alzheimer's disease, prion diseases, and Lewy body diseases...

The current ageing trend of the world population has, in part, accounted for Alzheimer disease (AD) being a public health issue in recent times. Although some progress has been made in clarifying AD-related pathophysiological mechanisms, effective intervention is still elusive. Biometals are indispensable to normal physiological functions of the human body-for example, neurogenesis and metabolism. However, their association with AD remains highly controversial. Copper (Cu) and zinc (Zn) are biometals that have been investigated at great length in relation to neurodegeneration, whereas less attention has been afforded to other trace biometals, such as molybdenum (Mo), and iodine...

BACKGROUND: Researches on diagnosis and treatment of Alzheimer's disease, the most common type of dementia, are still ongoing. Taurine is frequently used in Alzheimer's disease models due to its protective effects. Metal cation dyshomeostasis is an important etiological factor for Alzheimer's disease. Transthyretin protein is thought to act as a transporter for the Aβ protein that accumulates in the brain and is eliminated in the liver and kidneys via the LRP-1 receptor. However, the effect of taurine on this mechanisms is not fully known...

Alzheimer's disease (AD), also called senile dementia, is the most common neurological disorder. Around 50 million people, mostly of advanced age, are suffering from dementia worldwide and this is expected to reach 100-130 million between 2040 and 2050. AD is characterized by impaired glutamatergic and cholinergic neurotransmission, which is associated with clinical and pathological symptoms. AD is characterized clinically by loss of cognition and memory impairment and pathologically by senile plaques formed by Amyloid β deposits or neurofibrillary tangles (NFT) consisting of aggregated tau proteins...

Alzheimer's disease (AD) is a complex multifactorial neurodegenerative disease. Metal ion dyshomeostasis and Aβ aggregation have been proposed to contribute to AD progression. Metal ions can bind to Aβ and promote Aβ aggregation, and ultimately lead to neuronal death. Bifunctional (metal chelation and Aβ interaction) compounds are showing promise against AD. In this work, eleven new 3,3'-diamino-2,2'-bipyridine derivatives 4a-4k were synthesized, and evaluated as bifunctional agents for AD treatment...

Beyond the well-explored proposition of protein aggregation or amyloidosis as the central event in amyloidogenic diseases like Alzheimer's Disease (AD), and Type 2 Diabetes Mellitus (T2Dm); there are alternative hypotheses, now becoming increasingly evident, which suggest that the small biomolecules like redox noninnocent metals (Fe, Cu, Zn, etc.) and cofactors (Heme) have a definite influence in the onset and extent of such degenerative maladies. Dyshomeostasis of these components remains as one of the common features in both AD and T2Dm etiology...

The brain, composed of billions of neurons, is a complex network of interacting dynamical systems controlling all body functions. Neurons are the building blocks of the nervous system and their impairment of their functions could result in neurodegenerative disorders. Accumulating evidence shows an increase of brain-affecting disorders, still today characterized by poor therapeutic options. There is a strong urgency to find new alternative strategies to prevent progressive neuronal loss. Polyphenols, a wide family of plant compounds with an equally wide range of biological activities, are suitable candidates to counteract chronic degenerative disease in the central nervous system...

Based on previous work, a series of novel 5-(2-hydroxyphenyl)-2-phthalide-3(3H)-pyrazolones derivatives were identified as potential multifunctional therapeutic agents for Alzheimer's disease. Biological evaluation exhibited that these derivatives had great performance against MAO-B, Aβ1-42 aggregation, oxidative stress and metal ion dyshomeostasis. Among them, 10x was selected as the optimal agent for its excellent MAO-B inhibitory activity (IC50  = 0.41 μM, SI > 24...

Essential trace metals like zinc (Zn), iron (Fe), and copper (Cu) play an important physiological role in the metabolomics and healthy functioning of body organs, including the brain. However, abnormal accumulation of trace metals in the brain and dyshomeostasis in the different regions of the brain have emerged as contributing factors in neuronal degeneration, Aβ aggregation, and Tau formation. The link between these essential trace metal ions and the risk of AD has been widely studied, although the conclusions have been ambiguous...