Stress In Alzheimer's Disease Brain Research Articles

Modified Tacrine Derivatives as Multitarget-Directed Ligands for the Treatment of Alzheimer's Disease: Synthesis, Biological Evaluation, and Molecular Modeling Study.

To develop multitarget-directed ligands (MTDLs) as potential treatments for Alzheimer's disease (AD) and to shed light on the effect of the chromene group in designing these ligands, 35 new tacrine-chromene derivatives were designed, synthesized, and biologically evaluated. Compounds 5c and 5d exhibited the most desirable multiple functions for AD; they were strong hAChE inhibitors with IC50 values of 0.44 and 0.25 μM, respectively. Besides, their potent BuChE inhibitory activity was 10- and 5-fold more active than rivastigmine with IC50 = 0.08 and 0.14 μM, respectively. Moreover, they could bind to the peripheral anionic site (PAS), influencing Aβ aggregation and decreasing Aβ-related neurodegeneration, especially compound 5d, which was 8 times more effective than curcumin with IC50 = 0.74 μM and 76% inhibition at 10 μM. Compounds 5c and 5d showed strong BACE-1 inhibition at the submicromolar level with IC50 = 0.38 and 0.44 μM, respectively, which almost doubled the activity of curcumin. They also showed single-digit micromolar inhibitory activity against MAO-B with IC50 = 5.15 and 2.42 μM, respectively. They also had antioxidant activities and showed satisfactory metal-chelating properties toward Fe+2, Zn+2, and Cu+2, inhibiting oxidative stress in AD brains. Furthermore, compounds 5c and 5d showed acceptable relative safety upon normal cells SH-SY5Y and HepG2. It was shown that 5c and 5d were blood-brain barrier (BBB) penetrants by online prediction. Taken together, these multifunctional properties highlight that compounds 5c and 5d can serve as promising candidates for the further development of multifunctional drugs against AD.

Molecular Pathophysiology of Insulin Depletion, Mitochondrial Dysfunction, and Oxidative Stress in Alzheimer's Disease Brain.

Accumulating clinical data indicates that insulin resistance and diabetes mellitus (DM) are major risk factors for Alzheimer's disease (AD); however, the exact mechanisms on how insulin resistance and DM act as risk factors for AD remain unclear. Recent progress in gene expression profiling of AD brains revealed that brain insulin production and insulin signaling are significantly impaired, indicating that AD brain exhibits a feature of brain diabetes with depletion of brain insulin, which causes mitochondrial dysfunction with increased oxidative stress, thereby increasing sensitivity to peripheral diabetes. Such diabetic condition in early stage of AD brain can be exacerbated by peripheral diabetes, namely, through hyperglycemia, hyperinsulinemia, or impaired insulin response. In this chapter, I reviewed mitochondrial dysfunction and oxidative stress in AD brain and discussed how those events are involved in AD pathogenesis.

Antioxidant properties of natural polyphenols and their therapeutic potentials for Alzheimer's disease

Alzheimer's disease (AD) is the most prevalent neurodegenerative disease and most common cause of dementia. However, there is no known way to halt or cure the neurodegenerative disease. Oxidative stress is a cardinal hallmark of the disease and has been considered as therapeutic target for AD treatment. Several factors may contribute to oxidative stress in AD brains. First, mitochondrion is a key player that produces reactive oxygen species (ROS). Mitochondrial dysfunction found in AD patients may exaggerate generation of ROS and oxidative stress. Second, amyloid-beta peptide generates ROS in the presence of metal ions such as Fe(2+) and Cu(2+). Third, activated glial cells in AD brains may produce excessive amount of superoxide and nitric oxide through NADPH oxidase and inducible nitric oxide synthase, respectively. Increased ROS can cause damage to protein, lipid and nucleic acids. Numerous studies demonstrated that natural polyphenolic compounds protect against various neurotoxic insults in vitro and in vivo AD models. In these studies, dietary polyphenolic compounds exhibit neuroprotective effects through scavenging free radicals and increasing antioxidant capacity. Furthermore, they could facilitate the endogenous antioxidant system by stimulating transcription. Some epidemiological and clinical studies highlighted their therapeutic potential for AD treatment. In this review, we will briefly discuss causes of oxidative stress in AD brains, and describe antioxidant neuroprotective effects and therapeutic potential for AD of selected natural polyphenolic compounds.

β-Amyloid peptide increases levels of iron content and oxidative stress in human cell and Caenorhabditis elegans models of Alzheimer disease

Recent studies indicate that the deposition of β-amyloid peptide (Aβ) is related to the pathogenesis of Alzheimer disease (AD); however, the underlying mechanism is still not clear. The abnormal interactions of Aβ with metal ions such as iron are implicated in the process of Aβ deposition and oxidative stress in AD brains. In this study, we observed that Aβ increased the levels of iron content and oxidative stress in SH-SY5Y cells overexpressing the Swedish mutant form of human β-amyloid precursor protein (APPsw) and in Caenorhabditis elegans Aβ-expressing strain CL2006. Intracellular iron and calcium levels and reactive oxygen species and nitric oxide generation significantly increased in APPsw cells compared to control cells. The activity of superoxide dismutase and the antioxidant levels of APPsw cells were significantly lower than those of control cells. Moreover, iron treatment decreased cell viability and mitochondrial membrane potential and aggravated oxidative stress damage as well as the release of Aβ1–40 from the APPsw cells. The iron homeostasis disruption in APPsw cells is very probably associated with elevated expression of the iron transporter divalent metal transporter 1, but not transferrin receptor. Furthermore, the C. elegans with Aβ-expression had increased iron accumulation. In aggregate, these results demonstrate that Aβ accumulation in neuronal cells correlated with neuronal iron homeostasis disruption and probably contributed to the pathogenesis of AD.

Endothelial Dysfunction and Repair in Alzheimer-Type Neurodegeneration: Neuronal and Glial Control

Current theories state that Alzheimer's disease (AD) is a vascular disorder that initiates its pathology through cerebral microvascular abnormalities. Endothelial dysfunction caused by the injury or death of endothelial cells contributes to progression of AD. Also, functional relationships between neurons, glial cells, and vascular cells within so-called neurovascular unit are dramatically compromised in AD. Several recent studies have highlighted that endothelial cells might be the target for the toxic action of heavily aggregated proteins, glia-derived cytokines, and stimuli inducing oxidative and metabolic stress in AD brains. Here, we describe the properties of the brain endothelium that contribute to its specific functions in the central nervous system, and how endothelial-neuronal-glial cell interactions are compromised in the pathogenesis of AD. We also discuss the ways in which functioning of endothelial cells can be modulated in cerebral microvessels. Understanding of molecular mechanisms of endothelial injury and repair in AD would give us novel diagnostic biomarkers and pharmacological targets.

Metals, oxidative stress and neurodegenerative disorders

The neurodegenerative diseases, Alzheimer's disease (AD) and Parkinson's disease (PD), are age-related disorders characterized by the deposition of abnormal forms of specific proteins in the brain. AD is characterized by the presence of extracellular amyloid plaques and intraneuronal neurofibrillary tangles in the brain. Biochemical analysis of amyloid plaques revealed that the main constituent is fibrillar aggregates of a 39-42 residue peptide referred to as the amyloid-β protein (Aβ). PD is associated with the degeneration of dopaminergic neurons in the substantia nigra pars compacta. One of the pathological hallmarks of PD is the presence of intracellular inclusions called Lewy bodies that consist of aggregates of the presynaptic soluble protein called α-synuclein. There are various factors influencing the pathological depositions, and in general, the cause of neuronal death in neurological disorders appears to be multifactorial. However, it is clear, that the underlying factor in the neurological disorders is increased oxidative stress substantiated by the findings that the protein side-chains are modified either directly by reactive oxygen species (ROS) or reactive nitrogen species (RNS), or indirectly, by the products of lipid peroxidation. The increased level of oxidative stress in AD brain is reflected by the increased brain content of iron (Fe) and copper (Cu) both capable of stimulating free radical formation (e.g. hydroxyl radicals via Fenton reaction), increased protein and DNA oxidation in the AD brain, enhanced lipid peroxidation, decreased level of cytochrome c oxidase and advanced glycation end products (AGEs), carbonyls, malondialdehyde (MDA), peroxynitrite, and heme oxygenase-1 (HO-1). AGEs, mainly through their interaction with receptors for advanced glycation end products (RAGEs), further activate signaling pathways, inducing formation of proinflammatory cytokines such as interleukin-6 (IL-6). The conjugated aromatic ring of tyrosine residues is a target for free-radical attack, and accumulation of dityrosine and 3-nitrotyrosine has also been reported in AD brain. The oxidative stress linked with PD is supported by both postmortem studies and by studies showing the increased level of oxidative stress in the substantia nigra pars compacta, demonstrating thus the capacity of oxidative stress to induce nigral cell degeneration. Markers of lipid peroxidation include 4-hydroxy-trans-2-nonenal (HNE), 4-oxo-trans-2-nonenal (4-ONE), acrolein, and 4-oxo-trans-2-hexenal, all of which are well recognized neurotoxic agents. In addition, other important factors, involving inflammation, toxic action of nitric oxide (NO·), defects in protein clearance, and mitochondrial dysfunction all contribute to the etiology of PD. It has been suggested that several individual antioxidants or their combinations can be neuroprotective and decrease the risk of AD or slow its progression. The aim of this review is to discuss the role of redox metals Fe and Cu and non-redox metal zinc (Zn) in oxidative stress-related etiology of AD and PD. Attention is focused on the metal-induced formation of free radicals and the protective role of antioxidants [glutathione (GSH), vitamin C (ascorbic acid)], vitamin E (α-Tocopherol), lipoic acid, flavonoids [catechins, epigallocatechin gallate (EGCG)], and curcumin. An alternate hypothesis topic in AD is also discussed.

Redox proteomics studies of in vivo amyloid beta‐peptide animal models of Alzheimer's disease: Insight into the role of oxidative stress

Alzheimer's disease (AD) is an age-related neurodegenerative disease. AD is characterized by the presence of senile plaques, neurofibrillary tangles, and synaptic loss. Amyloid β-peptide (Aβ), a component of senile plaques, has been proposed to play an important role in oxidative stress in AD brain and could be one of the key factors in the pathogenesis of AD. In the present review, we discuss some of the AD animal models that express Aβ, and compare the proteomics-identified oxidatively modified proteins between AD brain and those of Aβ models. Such a comparison would allow better understanding of the role of Aβ in AD pathogenesis thereby helping in developing potential therapeutics to treat or delay AD.

Protein Oxidation and Lipid Peroxidation in Brain of Subjects with Alzheimer's Disease: Insights into Mechanism of Neurodegeneration from Redox Proteomics

Alzheimer's disease (AD), the leading cause of dementia, involves regionalized neuronal death, synaptic loss, and an accumulation of intraneuronal, neurofibrillary tangles and extracellular senile plaques. Although the initiating causes leading to AD are unknown, a number of previous studies reported the role of oxidative stress in AD brain. Postmortem analysis of AD brain showed elevated markers of oxidative stress including protein nitrotyrosine, carbonyls in proteins, lipid oxidation products, and oxidized DNA bases. In this review, we focus our attention on the role of protein oxidation and lipid peroxidation in the pathogenesis of AD. Particular attention is given to the current knowledge about the redox proteomics identification of oxidatively modified proteins in AD brain.

Phospholipases A2Mediate Amyloid-β Peptide-Induced Mitochondrial Dysfunction

Mitochondrial dysfunction has been implicated in the pathophysiology of Alzheimer's disease (AD) brains. To unravel the mechanism(s) underlying this dysfunction, we demonstrate that phospholipases A2 (PLA2s), namely the cytosolic and the calcium-independent PLA2s (cPLA2 and iPLA2), are key enzymes mediating oligomeric amyloid-beta peptide (Abeta(1-42))-induced loss of mitochondrial membrane potential and increase in production of reactive oxygen species from mitochondria in astrocytes. Whereas the action of iPLA2 is immediate, the action of cPLA2 requires a lag time of approximately 12-15 min, probably the time needed for initiating signaling pathways for the phosphorylation and translocation of cPLA2 to mitochondria. Western blot analysis indicated the ability of oligomeric Abeta(1-42) to increase phosphorylation of cPLA2 in astrocytes through the NADPH oxidase and mitogen-activated protein kinase pathways. The involvement of PLA2 in Abeta(1-42)-mediated perturbations of mitochondrial function provides new insights to the decline in mitochondrial function, leading to impairment in ATP production and increase in oxidative stress in AD brains.

Vitamin Ε as an Antioxidant/Free Radical Scavenger Against Amyloid β-Peptide-Induced Oxidative Stress in Neocortical Synaptosomal Membranes and Hippocampal Neurons in Culture: Insights into Alzheimer's Disease

Amyloid beta-peptide (Abeta), the major constituent in senile plaques in Alzheimer's disease (AD) brain, is thought by many researchers to be central to neurotoxicity in AD brain. Increasing evidence from many laboratories indicates that AD brain is under oxidative stress, with strong evidence of protein oxidation, lipid peroxidation, and peroxynitrite damage. A link between the central role of Abeta and oxidative stress in AD brain may be Abeta-associated free radical oxidative stress. If so, antioxidants such as vitamin E should modulate Abeta-induced oxidative damage and neurotoxicity in brain cells. This review summarizes studies of Abeta-associated free radical oxidative stress and its inhibition by vitamin E in cortical synaptosomal membranes and hippocampal neuronal cells in culture. Taken together with the recent report that vitamin E slows the progression of AD, this review strongly supports a central role of Abeta-associated free radical oxidative stress in neurotoxicity in AD brain.