Amyloid β-protein toxicity and oxidative stress in Alzheimer's disease

Behl, Christian

doi:10.1007/s004410050955

Cited by 197 publications

(143 citation statements)

References 125 publications

Supporting

Mentioning

136

Contrasting

Unclassified

Order By: Relevance

“…A promotes neurite outgrowth, generates reactive oxygen intermediates, induces cytotoxic cellular oxidative stress, and microglial activation (Koo et al, 1993;Behl, 1997;Sasaki et al, 1997). Although the mechanism by which A peptides cause enhanced expression of proinflammatory cytokines from microglia, is not fully understood there is evidence that A may interact with cell-surface receptors, including receptors for advanced glycosylated endproducts (RAGE) and scavenger receptors (El Khoury et al, 1996;Yan et al, 1996).…”

Section: Molecules Involved In Microglial Activation and Signal Transmentioning

confidence: 99%

Microglia, major player in the brain inflammation: their roles in the pathogenesis of Parkinson's disease

Kim

Joh²

2006

Exp Mol Med

581

450

View full text Add to dashboard Cite

Inflammation, a self-defensive reaction against various pathogenic stimuli, may become harmful self-damaging process. Increasing evidence has linked chronic inflammation to a number of neurodegenerative disorders including Alzheimer's disease (AD), Parkinson's disease (PD), and multiple sclerosis. In the central nervous system, microglia, the resident innate immune cells play major role in the inflammatory process. Although they form the first line of defense for the neural parenchyma, uncontrolled activation of microglia may directly toxic to neurons by releasing various substances such as inflammatory cytokines (IL-1β, TNF-α, IL-6), NO, PGE2, and superoxide. Moreover, our recent study demonstrated that activated microglia phagocytose not only damaged cell debris but also neighboring intact cells. It further supports their active participation in self-perpetuating neuronal damaging cycles. In the following review, we discuss microglial responses to damaging neurons, known activators released from injured neurons and how microglia cause neuronal degeneration. In the last part, microglial activation and their role in PD are discussed in depth.

show abstract

Section: Molecules Involved In Microglial Activation and Signal Transmentioning

confidence: 99%

Microglia, major player in the brain inflammation: their roles in the pathogenesis of Parkinson's disease

Kim

Joh²

2006

Exp Mol Med

581

450

View full text Add to dashboard Cite

show abstract

“…The molecular mechanisms by which A␤ contributes to oxidative damage remain unclear (11)(12)(13)(14)(15)(16)(17)(18)(19). Understanding these mechanisms, however, is critical for developing effective methods to manage the disease.…”

mentioning

confidence: 99%

Inhibitors of Catalase-Amyloid Interactions Protect Cells from β-Amyloid-Induced Oxidative Stress and Toxicity

Habib

Lee

Yang

2010

Journal of Biological Chemistry

101

120

View full text Add to dashboard Cite

Although oxidative stress is commonly associated with aging (1, 2), patients with Alzheimer disease (AD) 3 often exhibit increased oxidative damage (3-10) and subsequent neuronal loss in ␤-amyloid (A␤)-rich regions of the brain. The molecular mechanisms by which A␤ contributes to oxidative damage remain unclear (11)(12)(13)(14)(15)(16)(17)(18)(19). Understanding these mechanisms, however, is critical for developing effective methods to manage the disease. One mechanism for A␤-induced cellular oxidative stress proposes that A␤ peptides interact directly with cellular enzymes responsible for maintaining low physiological levels of reactive oxygen species (ROS) (20 -23). Two potential outcomes from such pathological protein-amyloid interactions are: 1) increased production of ROS, or 2) reduced degradation of ROS.The major ROS in cells are superoxide and the more reactive hydrogen peroxide (H 2 O 2 )-derived hydroxyl radical (24, 25). Both superoxide and H 2 O 2 are primarily produced in the mitochondria (26 -28). A␤ peptides have been shown to accumulate in the mitochondria (29, 30), and, therefore, could exert their detrimental effects through interaction with mitochondrial proteins (23, 31-34). Superoxide is produced by several enzymecatalyzed reactions in the mitochondria (25). Behl et al. (11) however, showed that a broad range of inhibitors of several of these enzymes had no effect on 〈␤ toxicity in clonal and primary neuronal cell cultures. Furthermore, Zhang et al. (35) reported that superoxide levels in cells were not substantially elevated upon exposure to 〈␤. These findings suggest that superoxide is not a dominant contributor to 〈␤ toxicity.On the other hand, 〈␤-induced cellular increase in H 2 O 2 or its metabolites is strongly correlated with 〈␤ toxicity (11, 13, 36). H 2 O 2 can be generated by several mitochondrial enzymes including monoamine oxidases, superoxide dismutase, and xanthine oxidase (25). Behl et al. (11) showed that inhibitors of monoamine oxidases and xanthine oxidase had no effect on 〈␤-induced H 2 O 2 accumulation or 〈␤ toxicity. Gsell et al. (37) also found that the activity of superoxide dismutase was unaltered in the brains of AD patients. Additionally, Rensink et al. (38) reported that the Dutch mutation of 〈␤ peptides (HCHWA-D 〈␤) did not bind directly to superoxide dismutase and Kaminsky et al. (39) reported only a relatively small effect of 〈␤ on superoxide dismutase activity and H 2 O 2 production upon chronic exposure of rat brains to 〈␤. These results suggest that 〈␤ peptides do not significantly affect production of H 2 O 2 in cells. Consequently, these findings imply that 〈␤-induced oxidative stress may arise from reduced degradation of H 2 O 2 in 〈␤-challenged cells.Degradation of H 2 O 2 in cells is primarily achieved by the enzymes catalase and glutathione peroxidase (GPx), both inside and outside of the mitochondria (25). Sagara et al. (40) found that cells resistant to 〈␤ toxicity had elevated levels of catalase and GPx. The activity of both enzymes was redu...

show abstract

“…Most studies examining A␤ toxicity in cell culture have used assays of neuronal viability, such as the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) reduction assay, which assesses cellular mitochondrial function (Liu et al, 1997). By using this approach and other techniques, A␤ has been shown to be neurotoxic in cell culture (Yankner, 1996;Behl, 1997). Several studies have implicated free radicals (Behl, 1997) or calcium (Mattson et al, 1992) in the neurotoxic mechanism.…”

mentioning

confidence: 99%

“…By using this approach and other techniques, A␤ has been shown to be neurotoxic in cell culture (Yankner, 1996;Behl, 1997). Several studies have implicated free radicals (Behl, 1997) or calcium (Mattson et al, 1992) in the neurotoxic mechanism. A number of studies have shown that A␤ toxicity is dependent on the degree of aggregation of the peptide (Pike et al, 1991;Lorenzo and Yankner, 1994).…”

mentioning

confidence: 99%

Substrate‐Bound β‐Amyloid Peptides Inhibit Cell Adhesion and Neurite Outgrowth in Primary Neuronal Cultures

Postuma

Nunan

et al. 2000

Journal of Neurochemistry

View full text Add to dashboard Cite

Accumulation of the ␤-amyloid protein (A␤) in the brain is an important step in the pathogenesis of Alzheimer's disease. However, the mechanism of A␤ toxicity remains unclear. A␤ can bind to the extracellular matrix, a structure that regulates adhesive events such as neurite outgrowth and synaptogenesis. The binding of A␤ to the extracellular matrix suggests that A␤ may disrupt cell-substrate interactions. Therefore, the effect of substrate-bound A␤ on the growth of isolated chick sympathetic and mouse cortical neurons was examined. A␤1-40 and A␤1-42 had dose-dependent effects on cell morphology. When tissue culture plates were coated with 0.1-10 ng/well A␤, neurite outgrowth increased. Higher amounts of A␤ peptides (Ն3 g/well) inhibited outgrowth. The inhibitory effect was related to aggregation of the peptide, as preincubation of A␤1-40 for 24 h at 37°C (a process known to increase amyloid fibril formation) was necessary for inhibition of neurite outgrowth. A␤29 -42, but not A␤1-28, also inhibited neurite outgrowth at high concentrations, demonstrating that the inhibitory domain is located within the hydrophobic C-terminal region. A␤1-40, A␤1-42, and A␤29 -42 also inhibited cell-substrate adhesion, indicating that the effect on neurite outgrowth may have been due to inhibition of cell adhesion. The results suggest that accumulation of A␤ may disrupt celladhesion mechanisms in vivo.

show abstract

Amyloid β-protein toxicity and oxidative stress in Alzheimer's disease

Cited by 197 publications

References 125 publications

Microglia, major player in the brain inflammation: their roles in the pathogenesis of Parkinson's disease

Microglia, major player in the brain inflammation: their roles in the pathogenesis of Parkinson's disease

Inhibitors of Catalase-Amyloid Interactions Protect Cells from β-Amyloid-Induced Oxidative Stress and Toxicity

Substrate‐Bound β‐Amyloid Peptides Inhibit Cell Adhesion and Neurite Outgrowth in Primary Neuronal Cultures

Contact Info

Product

Resources

About