Amyloid β-protein (Aβ)1-40 protects neurons from damage induced by Aβ1-42 in culture and in rat brain (original) (raw)
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Brain Research Reviews, 2003
Although much maligned, the amyloid-b (Ab) protein has been shown to possess a number of trophic properties that emanate from the protein's ability to bind Cu, Fe and Zn. Ab belongs to a group of proteins that capture redox metal ions (even under mildly acidotic conditions), thereby preventing them from participating in redox cycling with other ligands. The coordination of Cu appears to be crucial for Ab's own antioxidant activity that has been demonstrated both in vitro as well as in the brain, cerebrospinal fluid and plasma. The chelation of Cu by Ab would therefore be predicted to dampen oxidative stress in the mildly acidotic and oxidative environment that accompanies acute brain trauma and Alzheimer's disease (AD). Given that oxidative stress promotes Ab generation, the formation of diffuse amyloid plaques is likely to be a compensatory response to remove reactive oxygen species. This review weighs up the evidence supporting both the trophic and toxic properties of Ab, and while evidence for direct Ab neurotoxicity in vivo is scarce, we postulate that the product of Ab's antioxidant activity, hydrogen peroxide (H O), is likely to mediate toxicity as the levels of this oxidant rise with the 2 2 accumulation of Ab in the AD brain. We propose that metal ion chelators, antioxidants, antiinflammatories and amyloid-lowering drugs that target the reduction of H O and / or Ab generation may be efficacious in decreasing neurotoxicity. However, given the antioxidant 2 2 2? activity of Ab, we suggest that the excessive removal of Ab may prevent adequate chelation of metal ions and removal of O , leading to 2 enhanced, rather than reduced, neuronal oxidative stress.
Scientific Reports
Alzheimer’s disease (AD) is a type of dementia that affects memory, thinking and behavior. Symptoms eventually become severe enough to interfere with daily tasks. Understanding the etiology and pathogenesis of AD is necessary for the development of strategies for AD prevention and/or treatment, and modeling of this pathology is an important step in achieving this goal. β-amyloid peptide (Aβ) injection is a widely used approach for modeling AD. Nevertheless, it has been reported that the model constructed by injection of Aβ in combination with a prooxidant cocktail (ferrous sulfate, Aβ, and buthionine sulfoximine (BSO) (FAB)) best reflects the natural development of this disease. The relationship between oxidative stress and Aβ deposition and their respective roles in Aβ-induced pathology in different animal models of AD have been thoroughly investigated. In the current paper, we compared the effects of Aβ 1-42 alone with that of Aβ-associated oxidative stress induced by the FAB cock...
Free Radical Biology and Medicine, 2006
The amyloid cascade hypothesis suggests that the insoluble and fibrillar form of β-amyloid (Aβ) may play a primary pathogenic role in Alzheimer disease at the molecular level. However, neither the rate of dementia nor the extent of neuronal change seems to correlate with the levels of amyloidotic plaques (i.e., aggregated/fibrillar Aβ). Recent evidence suggests, however, that neurotoxicity may be exerted also by rather small soluble aggregates of Aβ, including oligomers. To characterize the mechanisms underlying toxicity mediated by the various aggregation states of Aβ peptides is then a major goal of research. In this work we investigated the effects of fibrillar, prefibrillar, and oligomeric Aβ 1-42 on the induction of oxidative stress, cell death, and BACE-1 expression in NT 2 neuronal cells. We found that prefibrillar and oligomeric Aβ 1-42 resulted in a more dramatic increase in the oxidative stress markers 4-hydroxynonenal and hydrogen peroxide compared to fibrillar Aβ 1-42 . Moreover, increased oxidative stress levels also resulted in a more rapid and significant induction of both apoptotic and necrotic neuronal cell death. Accordingly, fibrillar Aβ 1-42 , but not the soluble nonfibrillar forms, was the only condition able to up-regulate BACE-1 expression and activity.
The EMBO Journal, 2010
The amyloid peptides Ab 40 and Ab 42 of Alzheimer's disease are thought to contribute differentially to the disease process. Although Ab 42 seems more pathogenic than Ab 40 , the reason for this is not well understood. We show here that small alterations in the Ab 42 :Ab 40 ratio dramatically affect the biophysical and biological properties of the Ab mixtures reflected in their aggregation kinetics, the morphology of the resulting amyloid fibrils and synaptic function tested in vitro and in vivo. A minor increase in the Ab 42 :Ab 40 ratio stabilizes toxic oligomeric species with intermediate conformations. The initial toxic impact of these Ab species is synaptic in nature, but this can spread into the cells leading to neuronal cell death. The fact that the relative ratio of Ab peptides is more crucial than the absolute amounts of peptides for the induction of neurotoxic conformations has important implications for anti-amyloid therapy. Our work also suggests the dynamic nature of the equilibrium between toxic and non-toxic intermediates.
Journal of Neuroscience Research, 2006
Oxidative stress has been implicated in the pathophysiology of a number of diseases, including neurodegenerative disorders such as Alzheimer's disease (AD), a neurodegenerative disorder associated with cognitive decline and enhanced oxidative stress. Amyloid-beta peptide 1-42 (Ab 1-42), one of the main component of senile plaques, can induce in vitro and in vivo oxidative damage to neuronal cells through its ability to produce free radicals. The aim of this study was to investigate the protective effect of the xanthate D609 on Ab 1-42-induced protein oxidation by using a redox proteomics approach. D609 was recently found to be a free radical scavenger and antioxidant. In the present study, rat primary neuronal cells were pretreated with 50 lM of D609, followed by incubation with 10 lM Ab 1-42 for 24 hr. In the cells treated with Ab 1-42 alone, four proteins that were significantly oxidized were identified: glyceraldehyde-3-phosphate dehydrogenase, pyruvate kinase, malate dehydrogenase, and 14-3-3 zeta. Pretreatment of neuronal cultures with D609 prior to Ab 1-42 protected all the identified oxidized proteins in the present study against Ab 1-42-mediated protein oxidation. Therefore, D609 may ameliorate the Ab 1-42-induced oxidative modification. We discuss the implications of these Ab 1-42-mediated oxidatively modified proteins for AD pathology and for potential therapeutic intervention in this dementing disorder. V
Alzheimer's & Dementia, 2011
Cognitive impairment in Alzheimer's disease (AD) patients is associated with a decline in the levels of growth factors, impairment of axonal transport and marked degeneration of basal forebrain cholinergic neurons (BFCNs). Neurogenesis persists in the adult human brain, and the stimulation of regenerative processes in the CNS is an attractive prospect for neuroreplacement therapy in neurodegenerative diseases such as AD. Currently, it is still not clear how the pathophysiological environment in the AD brain affects stem cell biology. Previous studies investigating the effects of the b-amyloid (Ab) peptide on neurogenesis have been inconclusive, since both neurogenic and neurotoxic effects on progenitor cell populations have been reported. In this study, we treated pluripotent human embryonic stem (hES) cells with nerve growth factor (NGF) as well as with fibrillar and oligomeric Ab 1-40 and Ab 1-42 (nM-mM concentrations) and thereafter studied the differentiation in vitro during 28-35 days. The process applied real time quantitative PCR, immunocytochemistry as well as functional studies of intracellular calcium signaling. Treatment with NGF promoted the differentiation into functionally mature BFCNs. In comparison to untreated cells, oligomeric Ab 1-40 increased the number of functional neurons, whereas oligomeric Ab 1-42 suppressed the number of functional neurons. Interestingly, oligomeric Ab exposure did not influence the number of hES cell-derived neurons compared with untreated cells, while in contrast fibrillar Ab 1-40 and Ab 1-42 induced gliogenesis. These findings indicate that Ab 1-42 oligomers may impair the function of stem cellderived neurons. We propose that it may be possible for future AD therapies to promote the maturation of functional stem cell-derived neurons by altering the brain microenvironment with trophic support and by targeting different aggregation forms of Ab.
β-Amyloid(1-40)-induced neurodegeneration in the rat hippocampal neurons of the CA1 subfield
Acta Neuropathologica, 1998
Small volumes of solutions injected into the hippocampus produce dramatic degeneration in dentate gyrus neurons, but not in neurons of the CA1 subfield. The aim of the present study was to ascertain whether solutions with different fragments of the β-amyloid protein (Aβ) could produce further degeneration in areas beyond the dentate gyrus. It was found that 5 days after injection of an aqueous solution containing the Aβ 1-40 fragment into the hippocampus, long stretches of the CA1 subfield were either deprived of neurons or most of the neurons were degenerating. By contrast, in animals with deposits containing Aβ 1-28, Aβ 1-42 or water, neuronal degeneration or depletion only occurred in a reduced area around the place where the implant needle penetrated the CA1 subfield. In animals injected with Aβ 1-40, many profiles in the CA1 subfield and dentate gyrus were undergoing apoptosis, as seen using preparations processed by routine histology or the TUNEL technique for detection of fragmented DNA. In addition, there was higher infiltration by ED1-positive, activated microglia-macrophagic cells in Aβ 1-42 deposits than in deposits of Aβ 1-40. The present results suggest that the intrahippocampal injection of toxic Aβ fragments produces neuronal degeneration in the rat CA1 subfield when using the appropriate protocol, and, thus, can provide an in vivo model to investigate the neurotoxic effects of Aβ and for the evaluation of drugs with potential anti-neurodegenerative activity.
Brain Research, 2007
Alzheimer's disease (AD) is a chronic disorder with progressive neurodegeneration associated with aging and is characterized by fibrillar beta-amyloid (Aβ) deposits in the brain. Although the increased production of Aβ seems to play a noticeable role in AD pathogenesis and its progression, all the mechanisms which are involved in this extracellular Aβ elevation are not known completely. In the present study, we used adult hippocampal neuronal culture as an in vitro model which is favorable for adult neurodegenerative diseases' studies. We introduced a toxic concentration for fibrillar Aβ1-42 in adult neurons which was much lower from the toxic concentration in embryonic neurons. To determine the effect of fibrillar Aβ1-42 which is the most toxic part of amyloid plaques, on extracellular Aβ1-40, as the main part of βAPP proteolysis products, we treated the neurons with fibrillar Aβ1-42 at nontoxic concentrations of 2 × 10 − 6 , 2×10 − 5 and 2 × 10 − 4 μM and measured extracellular Aβ1-40. Our findings show that even very low levels of fibrillar Aβ1-42 can contribute to subsequent extracellular Aβ elevation in a dose dependent manner. These results suggest that even low levels of fibrillar Aβ may have deleterious actions if it remains in extracellular space for a period of time.
Neurochemical Research, 2009
Accumulation of the neurotoxic amyloid b-peptide (Ab) in the brain is a hallmark of Alzheimer's disease (AD). Several synthetic Ab peptides have been used to study the mechanisms of toxicity. Here, we sought to establish comparability between two commonly used Ab peptides Ab1-42 and Ab25-35 on an in vitro model of Ab toxicity. For this purpose we used organotypic slice cultures of rat hippocampus and observed that both Ab peptides caused similar toxic effects regarding to propidium iodide uptake and caspase-3 activation. In addition, we also did not observe any effect of both peptides on Akt and PTEN phosphorylation; otherwise the phosphorylation of GSK-3b was increased. Although further studies are necessary for understanding mechanisms underlying Ab peptide toxicity, our results provide strong evidence that Ab1-42 and the Ab25-35 peptides induce neural injury in a similar pattern and that Ab25-35 is a convenient tool for the investigation of neurotoxic mechanisms involved in AD.
β-Amyloid Monomers Are Neuroprotective
The Journal of Neuroscience, 2009
The 42-aa-long β-amyloid protein—Aβ1-42—is thought to play a central role in the pathogenesis of Alzheimer's disease (AD) (Walsh and Selkoe, 2007). Data from AD brain (Shankar et al., 2008), transgenic APP (amyloid precursor protein)-overexpressing mice (Lesné et al., 2006), and neuronal cultures treated with synthetic Aβ peptides (Lambert et al., 1998) indicate that self-association of Aβ1-42monomers into soluble oligomers is required for neurotoxicity. The function of monomeric Aβ1-42is unknown. The evidence that Aβ1-42is present in the brain and CSF of normal individuals suggests that the peptide is physiologically active (Shoji, 2002). Here we show that synthetic Aβ1-42monomers support the survival of developing neurons under conditions of trophic deprivation and protect mature neurons against excitotoxic death, a process that contributes to the overall neurodegeneration associated with AD. The neuroprotective action of Aβ1-42monomers was mediated by the activation of the PI...