Translation of the Alzheimer Amyloid Precursor Protein mRNA Is Up-regulated by Interleukin-1 through 5′-Untranslated Region Sequences

Rogers, Jack T.; Leiter, Lorene M.; McPhee, James T.; Cahill, Catherine M.; Zhan, Shanshan; Potter, Huntington; Nilsson, Lars

doi:10.1074/jbc.274.10.6421

Cited by 275 publications

(213 citation statements)

References 66 publications

(81 reference statements)

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“…For example, IL-1␤ is a glia-derived cytokine found at increased levels in AD pathology [5]. In addition, IL-1␤ increases production of the amyloid precursor protein [26], further enhances astrocyte activation [19], and brings about increased tau phosphorylation [12]. The suppression of IL-1␤ suggests one key pathway through which aminopyridazines could exert a therapeutic effect with later interventions.…”

Section: Discussionmentioning

confidence: 99%

Aminopyridazines inhibit β-amyloid-induced glial activation and neuronal damage in vivo

Craft

Watterson

Frautschy

et al. 2004

Neurobiology of Aging

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The critical role of chronic inflammation in disease progression continues to be increasingly appreciated across multiple disease areas, especially in neurodegenerative disorders such as Alzheimer's disease. We report that late intervention with a recently discovered aminopyridazine suppressor of glial activation, developed to inhibit both oxidative and inflammatory cytokine pathways, attenuates human amyloid beta (A␤)-induced glial activation in a murine model. Peripheral administration of the aminopyridazine MW01-070C, beginning 3 weeks after the start of intracerebroventricular infusion of human A␤1-42, decreased the number of activated astrocytes and microglia and the levels of proinflammatory cytokines interleukin-1␤, tumor necrosis factor-␣ and S100B in the hippocampus. Inhibition of neuroinflammation correlated with a decreased neuron loss, restoration towards control levels of synaptic dysfunction biomarkers in the hippocampus, and diminished amyloid plaque deposition. The results from this in vivo chemical biology approach provide a proof of concept that targeting of key glia inflammatory cytokine pathways can suppress A␤-induced neuroinflammation in vivo, with resultant attenuation of neuronal damage.

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Section: Discussionmentioning

confidence: 99%

Aminopyridazines inhibit β-amyloid-induced glial activation and neuronal damage in vivo

Craft

Watterson

Frautschy

et al. 2004

Neurobiology of Aging

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“…The mRNA was resuspended in deionized water and analyzed on agarose gels. For transcripts used in in vivo translation experiments, 7-methyl guanosine (Boehringer Mannheim) was added to the mixture and the concentration of GTP was reduced to 167 M. Radiolabeled probes were transcribed from 1 g of linearized DNA in the presence of 100 Ci of [␣- 32 The chloramphenicol acetyltransferase (CAT) antisense riboprobe used in the Northern blot analyses was synthesized in the presence of T7 RNA polymerase from the pGEM CAT linearized with PstI.…”

Section: Methodsmentioning

confidence: 99%

“…Radiolabeled 3ЈUTR-L (344 nt), 3Ј UTR-2G (88 nt), and 3Ј UTR-S (86 nt) were transcribed in vitro from the pSP64 APP plasmid restricted by BamHI, XmaI, and SmaI, respectively. [␣- 32 …”

Section: Methodsmentioning

confidence: 99%

A GG Nucleotide Sequence of the 3′ Untranslated Region of Amyloid Precursor Protein mRNA Plays a Key Role in the Regulation of Translation and the Binding of Proteins

Mbella

Bertrand

Huez

et al. 2000

Molecular and Cellular Biology

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The alternative polyadenylation of the mRNA encoding the amyloid precursor protein (APP) involved in Alzheimer's disease generates two molecules, with the first of these containing 258 additional nucleotides in the 3 untranslated region (3 UTR). We have previously shown that these 258 nucleotides increase the translation of APP mRNA injected in Xenopus oocytes (5). Here, we demonstrate that this mechanism occurs in CHO cells as well. We also present evidence that the 3 UTR containing 8 nucleotides more than the short 3 UTR allows the recovery of an efficiency of translation similar to that of the long 3 UTR. Moreover, the two guanine residues located at the 3 ends of these 8 nucleotides play a key role in the translational control. Using gel retardation mobility shift assay, we show that proteins from Xenopus oocytes, CHO cells, and human brain specifically bind to the short 3 UTR but not to the long one. The two guanine residues involved in the translational control inhibit this specific binding by 65%. These results indicate that there is a correlation between the binding of proteins to the 3 UTR of APP mRNA and the efficiency of mRNA translation, and that a GG motif controls both binding of proteins and translation.The control of gene expression governs cell differentiation. The first step of this control is provided by the transcription of specific genes. In eucaryotic cells, the scanning of a gene by the RNA polymerase II leads to the production of a nuclear transcript which, in most cases, will undergo three major modifications: capping of its 5Ј untranslated region (5ЈUTR), polyadenylation of the 3ЈUTR, and splicing of introns (13,38).At the postranscriptional level, the efficiency of translation of mature mRNA can also regulate gene expression. The phosphorylation of initiation factors of translation, which interact with the 5Ј end of mRNAs, has been demonstrated to modulate translation (21, 31).The presence of secondary structures in the 5ЈUTR can also influence mRNA translation either by increasing the binding affinity of some eucaryotic initiation factors (18) or by interacting with cellular proteins which can completely inhibit the initiation of translation (9,33).Although the 3ЈUTR is located downstream of the coding sequence, it has been widely demonstrated that this region can also modulate mRNA translation (41). The poly(A) tail is one element of the 3ЈUTR implicated in both the stability of mRNA and the regulation of its translation (34). The poly(A) tail can increase the stability of an mRNA molecule by protecting the mRNA from digestion by 3Ј35Ј exonucleases (7). A more dynamic role has been attributed to the poly(A) tail since it was demonstrated that its removal from the 3Ј end of capped mRNA decreases translation (22, 37). In Saccharomyces cerevisiae the enhancement of translation mediated by the poly(A) tail requires the formation of a complex between the poly(A) tail and a poly(A) binding protein (PABP) since the depletion of the PABP results in the inhibition of translation (36). This co...

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“…Oxidative stress is a common factor in both the aged brain and neurodegeneration and this partially may be due to the increased reactive gliosis that follows both conditions [49,85,86,103]. The prion glycoprotein, expressed on microglial cells, augments activation of these cells [17].…”

Section: Prion Proteinmentioning

confidence: 99%

“…The role of the protein in protecting neurons is supported by studies that show that A␤PP is upregulated during stressful conditions. The synthesis of A␤PP in astrocytes increases after treatment with IL-1 [86] and transient ischemic changes modulate the expression of A␤PP mRNA in rat cerebral cortex [58]. Amyloid-␤ is cleaved from A␤PP and cultured cells derived from the CNS constitutively produce A␤.…”

Section: Amyloid-␤ Proteinmentioning

confidence: 99%

Mechanisms by which metals promote events connected to neurodegenerative diseases

Campbell

Smith

Sayre

et al. 2001

Brain Research Bulletin

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Although the exact causative phenomenon responsible for the onset and progression of neurodegenerative disorders is at present unresolved, there are some clues as to the mechanisms underlying these chronic diseases. This review addresses mechanisms by which endogenous or environmental factors, through interaction with redox active metals, may initiate a common cascade of events terminating in neurodegeneration.

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Translation of the Alzheimer Amyloid Precursor Protein mRNA Is Up-regulated by Interleukin-1 through 5′-Untranslated Region Sequences

Cited by 275 publications

References 66 publications

Aminopyridazines inhibit β-amyloid-induced glial activation and neuronal damage in vivo

Aminopyridazines inhibit β-amyloid-induced glial activation and neuronal damage in vivo

A GG Nucleotide Sequence of the 3′ Untranslated Region of Amyloid Precursor Protein mRNA Plays a Key Role in the Regulation of Translation and the Binding of Proteins

Mechanisms by which metals promote events connected to neurodegenerative diseases

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