1,721,237 research outputs found
Close encounter: mitochondria, endoplasmic reticulum and Alzheimer's disease.
No full textEMBO J (2012) 31 21, 4106–4123. doi:; DOI: 10.1038/emboj.2012.202; published online August 14 2012 Alzheimer’s disease (AD) is characterized by the loss of hippocampal and cortical neurons as a consequence of the accumulation of amyloid-β (Aβ). Aβ is produced from the amyloid precursor protein (APP) by the γ-secretase complex components presenilin-1 (PS1) and -2 (PS2), which are mutated in genetic forms of AD. In this issue, Schon and coworkers show that PS1 and PS2 are located at the interface between mitochondria and endoplasmic reticulum (ER). In models of familial and sporadic AD, these two organelles are juxtaposed closely, affecting shared lipid metabolic pathways. The interface between mitochondria and ER emerges as a new potential determinant of AD pathogenesis.status: Publishe
microRNA-132: a key noncoding RNA operating in the cellular phase of Alzheimer's disease
No full textWith the consideration of the broad involvement of microRNAs (miRNAs) in the regulation of molecular networks in the brain, it is not surprising that miRNA dysregulation causes neurodegeneration in animal models. miRNA profiling in the human brain has revealed miR-132 as one of the most severely down-regulated miRNAs at the intermediate and late Braak stages of Alzheimer’s disease (AD), as well as in other neurodegenerative disorders. Suppression of miR-132 aggravates multiple layers of pathology at the molecular and functional level. We describe the potential therapeutic implications of these findings and suggest miRNA targeting or replacement as a realistic multi-hit, therapeutic strategy for AD. Salta, E., De Strooper, B. microRNA-132: a key noncoding RNA operating in the cellular phase of Alzheimer’s disease
The disintegrin/metalloprotease ADAM 10 is essential for Notch signalling but not for alpha-secretase activity in fibroblasts
No full textHartmann D, de Strooper B, Serneels L, et al. The disintegrin/metalloprotease ADAM 10 is essential for Notch signalling but not for alpha-secretase activity in fibroblasts. Human Molecular Genetics. 2002;11(21):2615-2624.The metalloprotease ADAM 10 is an important APP α-secretase candidate, but in vivo proof of this is lacking. Furthermore, invertebrate models point towards a key role of the ADAM 10 orthologues Kuzbanian and sup-17 in Notch signalling. In the mouse, this function is, however, currently attributed to ADAM 17/TACE, while the role of ADAM 10 remains unknown. We have created ADAM 10-deficient mice. They die at day 9.5 of embryogenesis with multiple defects of the developing central nervous system, somites, and cardiovascular system. In situ hybridization revealed a reduced expression of the Notch target gene hes-5 in the neural tube and an increased expression of the Notch ligand dll-1, supporting an important role for ADAM 10 in Notch signalling in the vertebrates as well. Since the early lethality precluded the establishment of primary neuronal cultures, APPsα generation was analyzed in embryonic fibroblasts and found to be preserved in 15 out of 17 independently generated ADAM 10-deficient fibroblast cell lines, albeit at a quantitatively more variable level than in controls, whereas a severe reduction was found in only two cases. The variability was not due to differences in genetic background or to variable expression of the alternative α-secretase candidates ADAM 9 and ADAM 17. These results indicate, therefore, either a regulation between ADAMs on the post-translational level or that other, not yet known, proteases are able to compensate for ADAM 10 deficiency. Thus, the observed variability, together with recent reports on tissue-specific expression patterns of ADAMs 9, 10 and 17, points to the existence of tissue-specific ‘teams’ of different proteases exerting α-secretase activity
Presenilin function in APP processing
No full textFamilial Alzheimer's disease (FAD) is now linked to at least three genes encoding the amyloid precursor protein (APP) on chromosome 21, and presenilin 1 and 2 on chromosome 14 and 1, respectively. FAD cases in whom presenilin mutations occur are more frequent than those with APP mutations. However, altogether they only account for approximately 0.1% of all the people suffering from Alzheimer's disease (AD),(1) and the causes of the remaining 99.9% of the sporadic form of AD or senile dementia remain unknown. Since FAD presents with the same neuropathological features as sporadic AD, i.e., cognitive impairments and the amyloid plaques and tangles in the brain, our working hypothesis is that similar molecular pathogenic mechanisms underly both sporadic and familial AD. It follows that APP and the presenilins must be key players in the disease. Detailed knowledge about the cell biology of these proteins will be a rich source of insight into the pathology of AD, but will also shed light on the fundamental neurobiology of these proteins
Presenilin function in APP processing
No full textFamilial Alzheimer's disease (FAD) is now linked to at least three genes encoding the amyloid precursor protein (APP) on chromosome 21, and presenilin 1 and 2 on chromosome 14 and 1, respectively. FAD cases in whom presenilin mutations occur are more frequent than those with APP mutations. However, altogether they only account for approximately 0.1% of all the people suffering from Alzheimer's disease (AD),(1) and the causes of the remaining 99.9% of the sporadic form of AD or senile dementia remain unknown. Since FAD presents with the same neuropathological features as sporadic AD, i.e., cognitive impairments and the amyloid plaques and tangles in the brain, our working hypothesis is that similar molecular pathogenic mechanisms underly both sporadic and familial AD. It follows that APP and the presenilins must be key players in the disease. Detailed knowledge about the cell biology of these proteins will be a rich source of insight into the pathology of AD, but will also shed light on the fundamental neurobiology of these proteins
Implication of APP secretases in notch signaling
No full textSignaling via notch receptors and their ligands is an evolutionary ancient and highly conserved mechanism governing cell-fate decisions throughout the animal kingdom. Upon ligand binding, notch receptors are subject to a two-step proteolysis essential for signal transduction. First, the ectodomain is removed by an enzyme cleaving near the outer-membrane surface ("site2"). Consecutively, the notch intracellular domain is liberated by a second protease cutting within the transmembrane sequence ("site3"). The intracellular domain is then transferred to the nucleus to act as a transcriptional coactivator. The proteases involved in notch receptor activation are shared with other proteins undergoing regulated intramembrane proteolysis, with intriguing parallels to APP. Specifically, site3 cleavage of Notch, as well as gamma-secretase processing of APP depend both critically on presenilins 1 and 2. Moreover, ADAM 10 and ADAM 17, the proteases proposed to perform site2 cleavage, are also the most probable candidate alpha-secretases to cleave APP. While the biological significance of APP processing remains to be further elucidated, interference with notch signaling has been shown to have severe consequences both in small animal models as well as in humans. Thus, a growing number of long known genetic syndromes like Alagille syndrome or Fallot's tetralogy can be caused by mutations of genes relevant for the notch signaling pathway. Likewise, the anticipated interference of gamma-secretase inhibitors with site3 cleavage may turn out to be a major obstacle for this therapeutic approach to Alzheimer's disease.status: Publishe
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
The disintegrins ADAM10 and TACE contribute to the constitutive and phorbol ester-regulated normal cleavage of the cellular prion protein
No full textWe showed previously that PrPc undergoes constitutive and phorbol ester-regulated cleavage inside the 106-126 toxic domain of the protein, leading to the production of a fragment referred to as N1. Here we show by a pharmacological approach that o-phenanthroline, a general zinc-metalloprotease inhibitors, as well as BB3103 and TAPI, the inhibitors of metalloenzymes ADAM10 (A disintegrin and metalloprotease); and TACE, tumor necrosis factor alpha -converting enzyme; ADAM17), respectively, drastically reduce N1 formation. We set up stable human embryonic kidney 293 transfectants overexpressing human ADAM10 and TACE, and we demonstrate that ADAM10 contributes to constitutive N1 roduction whereas TACE mainly participates in regulated N1 formation. Furthermore, constitutive N1 secretion is drastically reduced in fibroblasts deficient for ADAM10 whereas phorbol 12,13-dibutyrate-regulated N1 production is fully abolished in TACE-deficient cells. Altogether, our data demonstrate for the first time that disintegrins could participate in the catabolism of glycosyl phosphoinositide-anchored proteins such as PrPc. Second, our study identifies ADAM10 and ADAM17 as the protease candidates responsible for normal cleavage of PrPc. Therefore, these disintegrins could be seen as putative cellular targets of a therapeutic strategy aimed at increasing normal PrPc breakdown and thereby depleting cells of the putative 106-126 "toxic" domain of PrPc
Physiological processing of the prion protein: Regulation by protein kinase c agonists and involvement of disintegrins
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