Truncated and modified amyloid-beta species

Kummer, Markus P.; Heneka, Michael T.

doi:10.1186/alzrt258

Cited by 250 publications

(277 citation statements)

References 88 publications

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“…Briefly, after translation and assembly to the cytoplasm membrane, APP is cleaved by β-secretase originating sAPP and a β-APP C-terminal fragment. The latter is then cleaved by other secretases originating the Aβ peptides [55,56]. Here, we show that APP mRNA expression is decreased in AD patients PBMCs.…”

Section: Discussionmentioning

confidence: 83%

Decrease in APP and CP mRNA expression supports impairment of iron export in Alzheimer's disease patients

Guerreiro

Silva

Crespo

et al. 2015

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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Alzheimer's disease (AD) is a neurodegenerative disorder of still unknown etiology and the leading cause of dementia worldwide. Besides its main neuropathological hallmarks, a dysfunctional homeostasis of transition metals has been reported to play a pivotal role in the pathogenesis of this disease. Dysregulation of iron (Fe) metabolism in AD has been suggested, particularly at the level of cellular iron efflux. Herein, we intended to further clarify the molecular mechanisms underlying Fe homeostasis in AD. In order to achieve this goal, the expression of specific Fe metabolism-related genes directly involved in Fe regulation and export was assessed in peripheral blood mononuclear cells (PBMCs) from 73AD patients and 74 controls by quantitative PCR. The results obtained showed a significant decrease in the expression of aconitase 1 (ACO1; P=0.007); ceruloplasmin (CP; P<0.001) and amyloid-beta precursor protein (APP; P=0.006) genes in AD patients compared with healthy volunteers. These observations point out to a significant downregulation in the expression of genes associated with ferroportin-mediated cellular Fe export in PBMCs from AD patients, when compared to controls. Taken together, these findings support previous studies suggesting impairment of Fe homeostasis in AD, which may lead to cellular Fe retention and oxidative stress, a typical feature of this disease.

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Section: Discussionmentioning

confidence: 83%

Decrease in APP and CP mRNA expression supports impairment of iron export in Alzheimer's disease patients

Guerreiro

Silva

Crespo

et al. 2015

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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“…To be more precise, however, amyloid beta does not refer to a singular chemical substance, but to several, depending on the exact cleavage sites and post-translational modifications including oxidation, phosphorylation, nitration, racemization, isomerization, pyroglutamylation, and glycosylation [103]. For instance, the 42 amino acid version (Aβ 1–42 ) has a stronger propensity to aggregate than the 40 amino acid version (Aβ 1–40 ).…”

Section: Pathogenesis Of Dendritic Spine Loss In Alzheimer’s Diseasementioning

confidence: 99%

Analyzing dendritic spine pathology in Alzheimer’s disease: problems and opportunities

et al. 2015

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Synaptic failure is an immediate cause of cognitive decline and memory dysfunction in Alzheimer’s disease. Dendritic spines are specialized structures on neuronal processes, on which excitatory synaptic contacts take place and the loss of dendritic spines directly correlates with the loss of synaptic function. Dendritic spines are readily accessible for both in vitro and in vivo experiments and have, therefore, been studied in great detail in Alzheimer’s disease mouse models. To date, a large number of different mechanisms have been proposed to cause dendritic spine dysfunction and loss in Alzheimer’s disease. For instance, amyloid beta fibrils, diffusible oligomers or the intracellular accumulation of amyloid beta have been found to alter the function and structure of dendritic spines by distinct mechanisms. Furthermore, tau hyperphosphorylation and microglia activation, which are thought to be consequences of amyloidosis in Alzheimer’s disease, may also contribute to spine loss. Lastly, genetic and therapeutic interventions employed to model the disease and elucidate its pathogenetic mechanisms in experimental animals may cause alterations of dendritic spines on their own. However, to date none of these mechanisms have been translated into successful therapeutic approaches for the human disease. Here, we critically review the most intensely studied mechanisms of spine loss in Alzheimer’s disease as well as the possible pitfalls inherent in the animal models of such a complex neurodegenerative disorder.

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“…On one hand, aggresomes are known to protect cells from the potentially toxic effects of misfolded, typically polyubiquitinated, proteins. On the other, insoluble aggresomes have been shown to induce inflammation and apoptosis, which can promote pathologic processes (30,(35)(36)(37)(38). We hypothesized that aggresomes may function during vascularized organ transplantation because they have been detected in tissues exposed to ischemia or hemodynamic stress (39,40).…”

Section: Discussionmentioning

confidence: 99%

A20 suppresses vascular inflammation by recruiting proinflammatory signaling molecules to intracellular aggresomes

et al. 2015

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A20 protects against pathologic vascular remodeling by inhibiting the inflammatory transcription factor NF-kB. A20's function has been attributed to ubiquitin editing of receptor-interacting protein 1 (RIP1) to influence activity/stability. The validity of this mechanism was tested using a murine model of transplant vasculopathy and human cells. Mouse C57BL/6 aortae transduced with adenoviruses containing A20 (or b-galactosidase as a control) were allografted into major histocompatibility complex-mismatched BALB/c mice. Primary endothelial cells, smooth muscle cells, or transformed epithelial cells (all human) were transfected with wild-type A20 or with catalytically inactive mutants as a control. NF-kB activity and intracellular localization of RIP1 was monitored by reporter gene assay, immunofluorescent staining, and Western blotting. Native and catalytically inactive versions of A20 had similar inhibitory effects on NF-kB activity (270% vs. 276%; P > 0.05). A20 promoted localization of RIP1 to insoluble aggresomes in murine vascular allografts and in human cells (53% vs. 0%) without altering RIP1 expression, and this process was increased by the assembly of polyubiquitin chains (87% vs. 28%; P < 0.05). A20 captures polyubiquitinated signaling intermediaries in insoluble aggresomes, thus reducing their bioavailability for downstream NF-kB signaling. This novel mechanism contributes to protection from vasculopathy in transplanted organs treated with exogenous A20.-Enesa, K., Moll, H. P., Luong, L., Ferran, C., Evans, P. C. A20 suppresses vascular inflammation by recruiting proinflammatory signaling molecules to intracellular aggresomes.

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Truncated and modified amyloid-beta species

Cited by 250 publications

References 88 publications

Decrease in APP and CP mRNA expression supports impairment of iron export in Alzheimer's disease patients

Decrease in APP and CP mRNA expression supports impairment of iron export in Alzheimer's disease patients

Analyzing dendritic spine pathology in Alzheimer’s disease: problems and opportunities

A20 suppresses vascular inflammation by recruiting proinflammatory signaling molecules to intracellular aggresomes

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