Intraneuronal Aβ as a trigger for neuron loss: can this be translated into human pathology?

Bayer, Thomas A.; Wirths, Oliver

doi:10.1042/bst0390857

Cited by 36 publications

(29 citation statements)

References 46 publications

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“…These important biological effects have, not surprisingly, relevant clinical consequences, as indicated by the influence that these gene polymorphisms may exert on the onset and severity of several clinical pathological conditions, including AD [4,5,6,7]. Several studies have suggested that the production, oligomerization and extra- or intraneuronal deposition of β-amyloid peptide, along with intracellular neurofibrillary tangle formation, play central roles in AD [29,30]. Accumulating evidence suggests that inflammation may also play an important role in the initiation or progression of AD [31,32,33].…”

Section: Discussionmentioning

confidence: 99%

Effect of Proinflammatory Gene Polymorphisms on the Risk of Alzheimer's Disease

Flex¹,

Giovannini

Biscetti³

et al. 2013

Neurodegener Dis

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Background: A number of studies associate Alzheimer's disease (AD) with APOE polymorphism and alleles which favor the increased expression of immunological mediators such as cytokines or acute-phase proteins. Objective: In this study we evaluated the distribution of a set of functionally important polymorphisms of genes encoding prototypical inflammatory molecules in individuals with AD. We also investigated whether a synergistic effect of these proinflammatory gene polymorphisms on the risk of AD could be hypothesized. Methods: In a genetic association study that included 533 AD patients and 713 controls, the following gene polymorphisms were analyzed: C-reactive protein (CRP) 1059 G/C, interleukin 6 (IL6) -174 G/C, interleukin 1β (IL1B) -31 T/C, tumor necrosis factor α (TNF-α) -308 G/A, macrophage migration inhibitory factor (MIF) -173 G/C, monocyte chemoattractant protein 1 (CCL2) -2518 A/G, intercellular adhesion molecule 1 (ICAM1) 469 E/K, E-selectin (SELE) Ser128Arg, macrophage inflammatory protein 1α (CCL3) -906 T/A, matrix metalloproteinase 3 (MMP3) -1171 5A/6A and matrix metalloproteinase 9 (MMP9) -1562 C/T. Results: We found that IL6, IL1B, CCL2, CCL3, SELE, ICAM1, MMP3, and MMP9 gene polymorphisms were significantly and independently associated with AD. The association remained significant even after the Bonferroni correction. We also found that these proinflammatory polymorphisms were associated with different levels of risk for AD, depending on the number of high-risk genotypes concomitantly carried by a given individual. Conclusion: Proinflammatory genotypes might influence the development and progression of AD exerting a potential synergistic effect.

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Section: Discussionmentioning

confidence: 99%

Effect of Proinflammatory Gene Polymorphisms on the Risk of Alzheimer's Disease

Flex¹,

Giovannini

Biscetti³

et al. 2013

Neurodegener Dis

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“…Pathological hallmarks of AD include neurofibrillary tangles consisting of hyper-phosphorylated microtubule-associated protein tau [4,5] and extracellular amyloid plaques derived from amyloid precursor protein (APP), a widely expressed trans-membrane metalloprotein essential for neuronal growth, survival, post-injury and repair [6]. The main component of plaques is amyloid β (Aβ) peptide, (38–43 amino acids) generated by sequential cleavage of APP by β- and γ-secretase [7-10].…”

Section: Introductionmentioning

confidence: 99%

The systemic iron-regulatory proteins hepcidin and ferroportin are reduced in the brain in Alzheimer’s disease

Raha

Vaishnav

Friedland

et al. 2013

acta neuropathol commun

158

167

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BackgroundThe pathological features of the common neurodegenerative conditions, Alzheimer’s disease (AD), Parkinson’s disease and multiple sclerosis are all known to be associated with iron dysregulation in regions of the brain where the specific pathology is most highly expressed. Iron accumulates in cortical plaques and neurofibrillary tangles in AD where it participates in redox cycling and causes oxidative damage to neurons. To understand these abnormalities in the distribution of iron the expression of proteins that maintain systemic iron balance was investigated in human AD brains and in the APP-transgenic (APP-tg) mouse.ResultsProtein levels of hepcidin, the iron-homeostatic peptide, and ferroportin, the iron exporter, were significantly reduced in hippocampal lysates from AD brains. By histochemistry, hepcidin and ferroportin were widely distributed in the normal human brain and co-localised in neurons and astrocytes suggesting a role in regulating iron release. In AD brains, hepcidin expression was reduced and restricted to the neuropil, blood vessels and damaged neurons. In the APP-tg mouse immunoreactivity for ferritin light-chain, the iron storage isoform, was initially distributed throughout the brain and as the disease progressed accumulated in the core of amyloid plaques. In human and mouse tissues, extensive AD pathology with amyloid plaques and severe vascular damage with loss of pericytes and endothelial disruption was seen. In AD brains, hepcidin and ferroportin were associated with haem-positive granular deposits in the region of damaged blood vessels.ConclusionOur results suggest that the reduction in ferroportin levels are likely associated with cerebral ischaemia, inflammation, the loss of neurons due to the well-characterised protein misfolding, senile plaque formation and possibly the ageing process itself. The reasons for the reduction in hepcidin levels are less clear but future investigation could examine circulating levels of the peptide in AD and a possible reduction in the passage of hepcidin across damaged vascular endothelium. Imbalance in the levels and distribution of ferritin light-chain further indicate a failure to utilize and release iron by damaged and degenerating neurons.

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“…In addition to acting from the extracellular space, where it accumulates in the diseased brain, Aβ also has an intracellular site of action (Wirths et al, 2004). Indeed, as a result of uptake from the extracellular space or via its intracellular synthesis and processing, Aβ has been reported to accumulate within the cell (Pierrot et al, 2004; Bayer and Wirths, 2011; Kaminski Schierle et al, 2011). This intracellular Aβ is also neurotoxic and has been shown to target the ER and the mitochondria, inducing a stress response and causing permeability transition, respectively (Yao et al, 2009; Umeda et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

Alzheimer's disease-associated peptide Aβ42 mobilizes ER Ca2+ via InsP3R-dependent and -independent mechanisms

Jensen

Bultynck

Luyten

et al. 2013

Front. Mol. Neurosci.

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Dysregulation of Ca2+ homeostasis is considered to contribute to the toxic action of the Alzheimer's disease (AD)-associated amyloid-β-peptide (Aβ). Ca2+ fluxes across the plasma membrane and release from intracellular stores have both been reported to underlie the Ca2+ fluxes induced by Aβ42. Here, we investigated the contribution of Ca2+ release from the endoplasmic reticulum (ER) to the effects of Aβ42 upon Ca2+ homeostasis and the mechanism by which Aβ42 elicited these effects. Consistent with previous reports, application of soluble oligomeric forms of Aβ42 induced an elevation in intracellular Ca2+. The Aβ42-stimulated Ca2+ signals persisted in the absence of extracellular Ca2+ indicating a significant contribution of Ca2+ release from the ER Ca2+ store to the generation of these signals. Moreover, inositol 1,4,5-trisphosphate (InsP3) signaling contributed to Aβ42-stimulated Ca2+ release. The Ca2+ mobilizing effect of Aβ42 was also observed when applied to permeabilized cells deficient in InsP3 receptors, revealing an additional direct effect of Aβ42 upon the ER, and a mechanism for induction of toxicity by intracellular Aβ42.

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Intraneuronal Aβ as a trigger for neuron loss: can this be translated into human pathology?

Cited by 36 publications

References 46 publications

Effect of Proinflammatory Gene Polymorphisms on the Risk of Alzheimer's Disease

Effect of Proinflammatory Gene Polymorphisms on the Risk of Alzheimer's Disease

The systemic iron-regulatory proteins hepcidin and ferroportin are reduced in the brain in Alzheimer’s disease

Alzheimer's disease-associated peptide Aβ42 mobilizes ER Ca2+ via InsP3R-dependent and -independent mechanisms

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