Search results for "Amyloid"

The Metalloprotease Meprin β Is an Alternative β-Secretase of APP

2017

The membrane bound metalloprotease meprin β is important for collagen fibril assembly in connective tissue formation and for the detachment of the intestinal mucus layer for proper barrier function. Recent proteomic studies revealed dozens of putative new substrates of meprin β, including the amyloid precursor protein (APP). It was shown that APP is cleaved by meprin β in distinct ways, either at the β-secretase site resulting in increased levels of Aβ peptides, or at the N-terminus releasing 11 kDa, and 20 kDa peptide fragments. The latter event was discussed to be rather neuroprotective, whereas the ectodomain shedding of APP by meprin β reminiscent to BACE-1 is in line with the amyloid h…

Alzheimer's disease associated with sporadic cerebral amyloid angiopathy in an elderly patient

2015

2020

The term “amyloid” refers to proteinaceous deposits of peptides that might be generated from larger precursor proteins e.g., by proteolysis. Common to these peptides is a stable cross-β dominated secondary structure which allows self-assembly, leading to insoluble oligomers and lastly to fibrils. These highly ordered protein aggregates have been, for a long time, mainly associated with human neurodegenerative diseases such as Alzheimer’s disease (Amyloid-β peptides). However, they also exert physiological functions such as in release of deposited hormones in human beings. In the light of the rediscovery of our microbial commensals as important companions in health and disease, the fact that…

Detecting Protein Aggregation on Cells Surface: Concanavalin A Oligomers Formation

2009

A number of neurodegenerative diseases involve protein aggregation and amyloid formation. Recently evidence has emerged indicating small-transient prefibrillar oligomers as the primary pathogenic agents. Noteworthy, strict analogies exist between the behaviour of cells in culture treated with misfolded non-pathogenic proteins and in pathologic conditions, this instance together with the observation that the oligomers and fibrils are characterised by common structural features suggest that common mechanisms for cytotoxicity could exists and have to be perused in common interactions involved in aggregation.We here report an experimental study on ConcanavalinA (ConA) aggregation and its effect…

Genomic structure and functional characterization of the human ADAM10 promoter

2005

The ADAM10 gene encodes a membrane-bound disintegrin-metalloproteinase, which, after overexpression in an Alzheimer disease (AD) mouse model, prevents amyloid pathology and improves long-term potentiation and memory. Because enhancing ADAM10 expression appears to be a reasonable approach for treatment of AD, we functionally analyzed the ADAM10 gene. Both human and mouse ADAM10 genes comprise approximately 160 kbp, are composed of 16 exons, and are evolutionarily highly conserved within 500 bp upstream of either translation initiation site. By using luciferase reporter assays, we demonstrate that nucleotides -2179 to -1 upstream of the human ADAM10 translation initiation site represent a fun…

Strategies to gain novel Alzheimer’s disease diagnostics and therapeutics using modulators of ABCA transporters

2021

Adenosine-triphosphate-(ATP)-binding cassette (ABC) transport proteins are ubiquitously present membrane-bound efflux pumps that distribute endo- and xenobiotics across intra- and intercellular barriers. Discovered over 40 years ago, ABC transporters have been identified as key players in various human diseases, such as multidrug-resistant cancer and atherosclerosis, but also neurodegenerative diseases, such as Alzheimer���s disease (AD). Most prominent and well-studied are ABCB1, ABCC1, and ABCG2, not only due to their contribution to the multidrug resistance (MDR) phenotype in cancer, but also due to their contribution to AD. However, our understanding of other ABC transporters is limited…

Statins and the squalene synthase inhibitor zaragozic acid stimulate the non-amyloidogenic pathway of amyloid-beta protein precursor processing by su…

2010

Cholesterol-lowering drugs such as statins influence the proteolytic processing of the amyloid-beta protein precursor (AbetaPP) and are reported to stimulate the activity of alpha-secretase, the major preventive secretase of Alzheimer's disease. Statins can increase the alpha-secretase activity by their cholesterol-lowering properties as well as by impairment of isoprenoids synthesis. In the present study, we elucidate the contribution of these pathways in alpha-secretase activation. We demonstrate that zaragozic acid, a potent inhibitor of squalene synthase which blocks cholesterol synthesis but allows synthesis of isoprenoids, also stimulates alpha-secretase activity. Treatment of human n…

Brothers in arms: proBDNF/BDNF and sAPPα/Aβ-signaling and their common interplay with ADAM10, TrkB, p75NTR, sortilin, and sorLA in the progression of…

2021

Abstract Brain-derived neurotrophic factor (BDNF) is an important modulator for a variety of functions in the central nervous system (CNS). A wealth of evidence, such as reduced mRNA and protein level in the brain, cerebrospinal fluid (CSF), and blood samples of Alzheimer’s disease (AD) patients implicates a crucial role of BDNF in the progression of this disease. Especially, processing and subcellular localization of BDNF and its receptors TrkB and p75 are critical determinants for survival and death in neuronal cells. Similarly, the amyloid precursor protein (APP), a key player in Alzheimer’s disease, and its cleavage fragments sAPPα and Aβ are known for their respective roles in neuropro…

Shedding of the amyloid precursor protein-like protein APLP2 by disintegrin-metalloproteinases

2005

Cleavage of the amyloid precursor protein (APP) within the amyloid-beta (Aβ) sequence by the α-secretase prevents the formation of toxic Aβ peptides. It has been shown that the disintegrin-metalloproteinases ADAM10 and TACE (ADAM17) act as α-secretases and stimulate the generation of a soluble neuroprotective fragment of APP, APPsα. Here we demonstrate that the related APP-like protein 2 (APLP2), which has been shown to be essential for development and survival of mice, is also a substrate for both proteinases. Overexpression of either ADAM10 or TACE in HEK293 cells increased the release of neurotrophic soluble APLP2 severalfold. The strongest inhibition of APLP2 shedding in neuroblastoma c…

Constitutive and regulated α-secretase cleavage of Alzheimer’s amyloid precursor protein by a disintegrin metalloprotease

1999

Amyloid β peptide (Aβ), the principal proteinaceous component of amyloid plaques in brains of Alzheimer’s disease patients, is derived by proteolytic cleavage of the amyloid precursor protein (APP). Proteolytic cleavage of APP by a putative α-secretase within the Aβ sequence precludes the formation of the amyloidogenic peptides and leads to the release of soluble APPsα into the medium. By overexpression ofa disintegrinandmetalloprotease (ADAM), classified as ADAM 10, in HEK 293 cells, basal and protein kinase C-stimulated α-secretase activity was increased severalfold. The proteolytically activated form of ADAM 10 was localized by cell surface biotinylation in the plasma membrane, but the m…