scholarly journals Sp1 and Smad transcription factors co-operate to mediate TGF-β-dependent activation of amyloid-β precursor protein gene transcription

2004 ◽  
Vol 383 (2) ◽  
pp. 393-399 ◽  
Author(s):  
Fabian DOCAGNE ◽  
Cecilia GABRIEL ◽  
Nathalie LEBEURRIER ◽  
Sylvain LESNÉ ◽  
Yannick HOMMET ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Transcriptional Activity ◽  
Molecular Mechanisms ◽  
Transforming Growth Factor ◽  
Amyloid Β ◽  
Transforming Growth Factor Β ◽  
Precursor Protein ◽  
Transcriptional Level ◽  
Amyloid Β Peptide ◽  
Aβ Amyloid

Abnormal deposition of Aβ (amyloid-β peptide) is one of the hallmarks of AD (Alzheimer's disease). This peptide results from the processing and cleavage of its precursor protein, APP (amyloid-β precursor protein). We have demonstrated previously that TGF-β (transforming growth factor-β), which is overexpressed in AD patients, is capable of enhancing the synthesis of APP by astrocytes by a transcriptional mechanism leading to the accumulation of Aβ. In the present study, we aimed at further characterization of the molecular mechanisms sustaining this TGF-β-dependent transcriptional activity. We report the following findings: first, TGF-β is capable of inducing the transcriptional activity of a reporter gene construct corresponding to the +54/+74 region of the APP promoter, named APPTRE (APP TGF-β-responsive element); secondly, although this effect is mediated by a transduction pathway involving Smad3 (signalling mother against decapentaplegic peptide 3) and Smad4, Smad2 or other Smads failed to induce the activity of APPTRE. We also observed that the APPTRE sequence not only responds to the Smad3 transcription factor, but also the Sp1 (signal protein 1) transcription factor co-operates with Smads to potentiate the TGF-β-dependent activation of APP. TGF-β signalling induces the formation of nuclear complexes composed of Sp1, Smad3 and Smad4. Overall, the present study gives new insights for a better understanding of the fine molecular mechanisms occurring at the transcriptional level and regulating TGF-β-dependent transcription. In the context of AD, our results provide additional evidence for a key role for TGF-β in the regulation of Aβ production.

Protein–protein interactions in the assembly and subcellular trafficking of the BACE (β-site amyloid precursor protein-cleaving enzyme) complex of Alzheimer's disease

2007 ◽  
Vol 35 (5) ◽  
pp. 974-979 ◽  
Author(s):  
R.B. Parsons ◽  
B.M. Austen
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Precursor Protein ◽  
Protein Interactions ◽  
Senile Plaques ◽  
Amyloid Β ◽  
Precursor Protein ◽  
Amyloid Β Peptide ◽  
Aβ Amyloid ◽  
Ad Alzheimer’S Disease

The correct assembly of the BACE (β-site amyloid precursor protein-cleaving enzyme or β-secretase) complex and its subsequent trafficking to cellular compartments where it associates with the APP (amyloid precursor protein) is essential for the production of Aβ (amyloid β-peptide), the protein whose aggregation into senile plaques is thought to be responsible for the pathogenesis of AD (Alzheimer's disease). These processes rely upon both transient and permanent BACE–protein interactions. This review will discuss what is currently known about these BACE–protein interactions and how they may reveal novel therapeutic targets for the treatment of AD.

Impairment of the activity of the plasma membrane Ca2+-ATPase in Alzheimer's disease

2011 ◽  
Vol 39 (3) ◽  
pp. 819-822 ◽  
Author(s):  
Ana M. Mata ◽  
María Berrocal ◽  
M. Rosario Sepúlveda
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Plasma Membrane ◽  
Molecular Mechanisms ◽  
Neurodegenerative Disorder ◽  
Senile Plaques ◽  
Amyloid Β ◽  
Inhibitory Effect ◽  
Amyloid Β Peptide ◽  
Aβ Amyloid

AD (Alzheimer's disease) is an age-associated neurodegenerative disorder where the accumulation of neurotoxic Aβ (amyloid β-peptide) in senile plaques is a typical feature. Recent studies point out a relationship between Aβ neurotoxicity and Ca2+ dyshomoeostasis, but the molecular mechanisms involved are still under discussion. The PMCAs (plasma membrane Ca2+-ATPases) are a multi-isoform family of proteins highly expressed in brain that is implicated in the maintenance of low intraneural Ca2+ concentration. Therefore the malfunction of this pump may also be responsible for Ca2+ homoeostasis failure in AD. We have found that the Ca2+-dependence of PMCA activity is affected in human brains diagnosed with AD, being related to the enrichment of Aβ. The peptide produces an inhibitory effect on the activity of PMCA which is isoform-specific, with the greatest inhibition of PMCA4. Besides, cholesterol blocked the inhibitory effect of Aβ, which is consistent with the lack of any Aβ effect on PMCA4 found in cholesterol-enriched lipid rafts isolated from pig brain. These observations suggest that PMCAs are a functional component of the machinery that leads to Ca2+ dysregulation in AD and propose cholesterol enrichment in rafts as a protector of the Aβ-mediated inhibition on PMCA.

Novel heparan sulphate analogues: inhibition of β-secretase cleavage of amyloid precursor protein

2005 ◽  
Vol 33 (5) ◽  
pp. 1116-1118 ◽  
Author(s):  
S.J. Patey ◽  
E.A. Yates ◽  
J.E. Turnbull
Keyword(s):  
Amyloid Precursor Protein ◽  
Heparan Sulphate ◽  
Amyloid Β ◽  
Precursor Protein ◽  
Amyloid Β Peptide ◽  
Neuritic Plaques ◽  
Rate Limiting Step ◽  
Aβ Amyloid ◽  
Ad Alzheimer’S Disease

The role of HS (heparan sulphate) in the pathology of AD (Alzheimer's disease) is multifaceted. HS and other glycosaminoglycans have been widely reported to be associated with neuritic plaques. HS has also been shown to promote the aggregation of Aβ (amyloid β-peptide), the proteinaceous component of neuritic plaques. Recently, we described a novel and contrasting role for HS in the pathology of AD: HS can inhibit the formation of Aβ, by directly interacting with the protease BACE1 (β-site amyloid precursor protein cleaving enzyme 1; β-secretase 1), that cleaves the amyloid precursor protein and is the rate limiting step in the generation of Aβ. Here, we review the current roles of HS and the potential for HS-derivatives in the treatment of AD.

Ca2+ enhances Aβ polymerization rate and fibrillar stability in a dynamic manner

2013 ◽  
Vol 450 (1) ◽  
pp. 189-197 ◽  
Author(s):  
Kristoffer Brännström ◽  
Anders Öhman ◽  
Malin Lindhagen-Persson ◽  
Anders Olofsson
Keyword(s):  
Self Assembly ◽  
Molecular Mechanisms ◽  
Amyloid Β ◽  
Mechanistic Explanation ◽  
Elongation Rate ◽  
Polymerization Rate ◽  
Amyloid Β Peptide ◽  
Aβ Amyloid ◽  
Ad Alzheimer’S Disease

Identifying factors that affect the self-assembly of Aβ (amyloid-β peptide) is of utmost importance in the quest to understand the molecular mechanisms causing AD (Alzheimer's disease). Ca2+ has previously been shown to accelerate both Aβ fibril nucleation and maturation, and dysregulated Ca2+ homoeostasis frequently correlates with development of AD. The mechanisms regarding Ca2+ binding, as well as its effect on fibril kinetics, are not fully understood. Using a polymerization assay we show that Ca2+ in a dynamic and reversible manner enhances both the elongation rate and fibrillar stability, where specifically the ‘dock and lock’ phase mechanism is enhanced. Through NMR analysis we found that Ca2+ affects the fibrillar architecture. In addition, and unexpectedly, we found that Ca2+ does not bind the free Aβ monomer. This implies that Ca2+ binding requires an architecture adopted by assembled peptides, and consequently is mediated through intermolecular interactions between adjacent peptides. This gives a mechanistic explanation to the enhancing effect on fibril maturation and indicates structural similarities between prefibrillar structures and mature amyloid. Taken together we show how Ca2+ levels affect the delicate equilibrium between the monomeric and assembled Aβ and how fluctuations in vivo may contribute to development and progression of the disease.

scholarly journals Role of peroxisome proliferator-activated receptor γ in amyloid precursor protein processing and amyloid β-mediated cell death

2005 ◽  
Vol 391 (3) ◽  
pp. 693-698 ◽  
Author(s):  
Cristina d'Abramo ◽  
Sara Massone ◽  
Jean-Marc Zingg ◽  
Antonio Pizzuti ◽  
Philippe Marambaud ◽  
...  
Keyword(s):  
Cultured Cells ◽  
Amyloid Β ◽  
Precursor Protein ◽  
Amyloid Precursor Protein Processing ◽  
Transcriptional Level ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Aβ Amyloid ◽  
Pparγ Agonists ◽  
Amyloid Cascade

Recent data indicate that PPARγ (peroxisome proliferator-activated receptor γ) could be involved in the modulation of the amyloid cascade causing Alzheimer's disease. In the present study we show that PPARγ overexpression in cultured cells dramatically reduced Aβ (amyloid-β) secretion, affecting the expression of the APP (Aβ precursor protein) at a post-transcriptional level. APP down-regulation did not involve the pathway of the secretases and correlated with a significant induction of APP ubiquitination. Additionally, we demonstrate that PPARγ was able to protect the cells from H2O2-induced necrosis by decreasing Aβ secretion. Taken together, our results indicate a novel mechanism at the basis of the neuroprotection shown by PPARγ agonists and an additional pathogenic role for Aβ accumulation.

The Alzheimer's Disease Amyloid Precursor Protein and its Neuritogenic Actions

2021 ◽  
Vol 18 ◽  
Author(s):  
Luan Luu ◽  
Giuseppe D. Ciccotosto ◽  
Roberto Cappai
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Nervous System ◽  
Amyloid Precursor Protein ◽  
Molecular Mechanisms ◽  
Amyloid Β ◽  
Normal Function ◽  
Precursor Protein ◽  
Amyloid Β Peptide ◽  
Neuronal Functions

: The Amyloid Precursor Protein (APP) is principally known and studied for its involve- ment in Alzheimer’s disease as the source of the amyloid β peptide; however, its physiological ac- tions within the nervous system are also important as it is involved in a range of neuronal activi- ties, including neurogenesis, synaptic plasticity, neurite outgrowth, and neuroprotection. Of the dif- ferent neuronal functions that APP can affect, some may be relevant to APP’s role in Alzheimer’s disease, while others can be primarily related to its physiological roles. This review will focus on APP’s neuritogenic actions and surmise the key molecular mechanisms, as well as the structural and signaling requirements, which form the basis for APP’s neuritogenic effects. Deciphering the normal function(s) of APP is valuable to properly understanding its role in health as well as Alzheimer’s disease.

scholarly journals Membrane microdomain switching: a regulatory mechanism of amyloid precursor protein processing

2008 ◽  
Vol 183 (2) ◽  
pp. 339-352 ◽  
Author(s):  
Takashi Sakurai ◽  
Kumi Kaneko ◽  
Misako Okuno ◽  
Koji Wada ◽  
Taku Kashiyama ◽  
...  
Keyword(s):  
Amyloid Precursor Protein ◽  
Molecular Mechanisms ◽  
Amyloid Β ◽  
Precursor Protein ◽  
Amyloid Precursor Protein Processing ◽  
Amyloid Β Peptide ◽  
Dependent Manner ◽  
App Processing ◽  
Membrane Microdomain ◽  
Activity Dependent

Neuronal activity has an impact on β cleavage of amyloid precursor protein (APP) by BACE1 to generate amyloid-β peptide (Aβ). However, the molecular mechanisms underlying this effect remain to be elucidated. Cholesterol dependency of β cleavage prompted us to analyze immunoisolated APP-containing detergent-resistant membranes from rodent brains. We found syntaxin 1 as a key molecule for activity-dependent regulation of APP processing in cholesterol-dependent microdomains. In living cells, APP associates with syntaxin 1–containing microdomains through X11–Munc18, which inhibits the APP–BACE1 interaction and β cleavage via microdomain segregation. Phosphorylation of Munc18 by cdk5 causes a shift of APP to BACE1-containing microdomains. Neuronal hyperactivity, implicated in Aβ overproduction, promotes the switching of APP microdomain association as well as β cleavage in a partially cdk5-dependent manner. We propose that microdomain switching is a mechanism of cholesterol- and activity-dependent regulation of APP processing in neurons.

Roles of proteolysis and lipid rafts in the processing of the amyloid precursor protein and prion protein

2005 ◽  
Vol 33 (2) ◽  
pp. 335-338 ◽  
Author(s):  
N.M. Hooper
Keyword(s):  
Amyloid Precursor Protein ◽  
Lipid Rafts ◽  
Prion Protein ◽  
Amyloid Β ◽  
Precursor Protein ◽  
Amyloid Β Peptide ◽  
Copper Binding ◽  
Secretase Activity ◽  
Aβ Amyloid ◽  
A Disintegrin And Metalloproteinase

In the amyloidogenic pathway, the APP (amyloid precursor protein) is proteolytically processed by the β- and γ-secretases to release the Aβ (amyloid-β) peptide that is neurotoxic and aggregates in the brains of patients suffering from Alzheimer's disease. In the non-amyloidogenic pathway, APP is cleaved by α-secretase within the Aβ domain, precluding deposition of intact Aβ peptide. The cellular form of the PrPC (prion protein) undergoes reactive oxygen species-mediated β-cleavage within the copper-binding octapeptide repeats or, alternatively, α-cleavage within the central hydrophobic neurotoxic domain. In addition, PrPC is shed from the membrane by the action of a zinc metalloprotease. Members of the ADAM (a disintegrin and metalloproteinase) family of zinc metalloproteases, notably ADAM10 and TACE (ADAM17) display α-secretase activity towards APP and appear to be responsible for the α-cleavage of PrPC. The amyloidogenic cleavage of APP by the β- and γ-secretases appears to occur preferentially in cholesterol-rich lipid rafts, while the conversion of PrPC into the infectious form PrPSc also appears to occur in these membrane domains.

scholarly journals Glycosaminoglycan Therapy Prevents TGF-β1 Overexpression and Pathologic Changes in Renal Tissue of Long-Term Diabetic Rats

2000 ◽  
Vol 11 (12) ◽  
pp. 2324-2336
Author(s):  
MONICA CEOL ◽  
GIOVANNI GAMBARO ◽  
ULRICH SAUER ◽  
BRUNO BAGGIO ◽  
FRANCA ANGLANI ◽  
...  
Keyword(s):  
High Glucose ◽  
Molecular Mechanisms ◽  
Transforming Growth Factor ◽  
Dermatan Sulfate ◽  
Mesangial Cells ◽  
Anticoagulant Activity ◽  
Transforming Growth Factor Β ◽  
Transcriptional Level ◽  
Diabetic Glomerulosclerosis ◽  
Tgf Β1

Abstract. Chronic induction of the prosclerotic cytokine transforming growth factor β (TGF-β) has been implicated in the pathogenesis of diabetic nephropathy. In a rat model of diabetes mellitus-induced glomerulosclerosis, daily administration of a modified heparin (mH) glycosaminoglycan (GAG) preparation with low anticoagulant activity prevented glomerular and tubular matrix accumulation, as well as overexpression of TGF-β1 mRNA and albuminuria, without obvious side effects. To elucidate the molecular mechanisms of GAG/mH inhibitory actions on TGF-β1, studies using cultured mesangial cells were also performed. In these cells, high glucose-induced, dose-dependent increases in TGF-β1 mRNA and bioactive TGF-β protein expression were inhibited by GAG/mH treatment, whereas basal TGF-β1 expression was not affected. Both the heparin-derived GAG and dermatan sulfate were effective, indicating that the heparin chemical structure is not necessary for inhibitory activity. Coincubation of GAG with active TGF-β1 demonstrated no inhibitory effect on TGF-β1 bioactivity, excluding a neutralizing effect of GAG on TGF-β1 at the protein level. Furthermore, it was demonstrated that GAG inhibited phorbol myristate acetate-induced translocation of protein kinase C-α (PKC-α) and -β1 and activation of PKC-α, as well as high glucose-induced activation of PKC-α. These results suggest that GAG inhibit TGF-β1 overexpression at the transcriptional level, possibly via inhibition of high glucose-activated PKC. The findings indicate the potential of GAG therapy for the prevention of diabetic glomerulosclerosis by the inhibition of chronic disease-induced TGF-β1 mRNA overexpression.

scholarly journals Phosphoproteome Profiling of Transforming Growth Factor (TGF)-β Signaling: Abrogation of TGFβ1-dependent Phosphorylation of Transcription Factor-II-I (TFII-I) Enhances Cooperation of TFII-I and Smad3 in Transcription

2005 ◽  
Vol 16 (10) ◽  
pp. 4765-4780 ◽  
Author(s):  
Taras Stasyk ◽  
Anna Dubrovska ◽  
Marta Lomnytska ◽  
Ihor Yakymovych ◽  
Christer Wernstedt ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Growth Factor ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Cyclin D3 ◽  
Luciferase Reporter ◽  
Transcriptional Level ◽  
Tgfβ Signaling ◽  
Factor Ii ◽  
Cytoskeletal Rearrangements

Transforming growth factor-β (TGFβ) signaling involves activation of a number of signaling pathways, several of which are controlled by phosphorylation events. Here, we describe a phosphoproteome profiling of MCF-7 human breast epithelial cells treated with TGFβ1. We identified 32 proteins that change their phosphorylation upon treatment with TGFβ1; 26 of these proteins are novel targets of TGFβ1. We show that Smad2 and Smad3 have different effects on the dynamics of TGFβ1-induced protein phosphorylation. The identified proteins belong to nine functional groups, e.g., proteins regulating RNA processing, cytoskeletal rearrangements, and proteasomal degradation. To evaluate the proteomics findings, we explored the functional importance of TGFβ1-dependent phosphorylation of one of the targets, i.e., transcription factor-II-I (TFII-I). We confirmed that TGFβ1 stimulated TFII-I phosphorylation at serine residues 371 and 743. Abrogation of the phosphorylation by replacement of Ser371 and Ser743 with alanine residues resulted in enhanced complex formation between TFII-I and Smad3, and enhanced cooperation between TFII-I and Smad3 in transcriptional regulation, as evaluated by a microarray-based measurement of expression of endogenous cyclin D2, cyclin D3, and E2F2 genes, and by a luciferase reporter assay. Thus, TGFβ1-dependent phosphorylation of TFII-I may modulate TGFβ signaling at the transcriptional level.

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