Search results for "Amyloid Precursor Protein"
showing 10 items of 134 documents
The Alzheimer’s disease associated bacterial protease RgpB from P. gingivalis activates the alternative β-secretase meprin β thereby increasing Aβ ge…
2019
AbstractAlzheimer’s disease (AD) is the most common type of dementia and characterized by tau hyperphosphorylation, oxidative stress, reactive microglia and amyloid-β (Aβ) deposits. A recent study revealed that Porphyromonas gingivalis infection is associated with amyloid β generation in Alzheimer’s disease. Increased Aβ levels, tau degradation and neuronal toxicity were observed as a consequence of ginigipain R (RgpB) activity, a cysteine protease constitutively secreted by P. gingivalis. Of note, we previously identified RgpB as a potent activator of the metalloproteinase meprin β. Interestingly, meprin β is an alternative β-secretase of the amyloid precursor protein (APP), which together…
ADAM10, myelin-associated metalloendopeptidase
2013
Publisher Summary This chapter discusses the structural chemistry and the biological aspects of ADAM10. Originally, ADAM10 was characterized as a myelin-associated metalloproteinase. After cloning the bovine ADAM10 cDNA, the deduced amino acid sequence indicated that the enzyme belonged to the reprolysin subfamily and therefore was named MADM (mammalian disintegrin metalloprotease). The mammalian reprolysin subfamily has been named ADAM (a disintegrin and metalloproteinase) and MADM has been designated ADAM10. The ADAM10 homologs in Drosophila melanogaster and Caenorhabditis elegans are named kuzbanian and sup-17, respectively. The enzymatic activity of isolated ADAM10 can be monitored in v…
Changing fate
2020
Abstract The alpha-secretase A disintegrin and metalloproteinase 10 (ADAM10) and the beta-secretase beta-APP cleaving enzyme 1 (BACE-1) compete in neurons to cleave the amyloid precursor protein (APP). The reaction started by BACE-1, designated the amyloidogenic pathway, leads to formation of neurotoxic amyloid beta peptides (A-betas), while alpha-secretase prevents this and gives rise to an alternative cleavage product (APPs-alpha, nonamyloidogenic pathway). The latter is also known to have neurotrophic and neuroprotective properties. Therefore, identification of mechanisms that lead to a switch in APP processing from the amyloidogenic to the nonamyloidogenic pathway is an attractive avenu…
Structural basis for the sheddase function of human meprin β metalloproteinase at the plasma membrane.
2012
Ectodomain shedding at the cell surface is a major mechanism to regulate the extracellular and circulatory concentration or the activities of signaling proteins at the plasma membrane. Human meprin β is a 145-kDa disulfide-linked homodimeric multidomain type-I membrane metallopeptidase that sheds membrane-bound cytokines and growth factors, thereby contributing to inflammatory diseases, angiogenesis, and tumor progression. In addition, it cleaves amyloid precursor protein (APP) at the β-secretase site, giving rise to amyloidogenic peptides. We have solved the X-ray crystal structure of a major fragment of the meprin β ectoprotein, the first of a multidomain oligomeric transmembrane sheddase…
Synthesis of a potent photoreactive acidic γ-secretase modulator for target identification in cells.
2012
Supramolecular self-assembly of amyloidogenic peptides is closely associated with numerous pathological conditions. For instance, Alzheimer´s disease (AD) is characterized by abundant amyloid plaques originating from the proteolytic cleavage of the amyloid precursor protein (APP) by β- and γ-secretases. Compounds named γ-secretase modulators (GSMs) can shift the substrate cleavage specificity of γ-secretase toward the production of non-amyloidogenic, shorter Aβ fragments. Herein, we describe the synthesis of highly potent acidic GSMs, equipped with a photoreactive diazirine moiety for photoaffinity labeling. The probes labeled the N-terminal fragment of presenilin (the catalytic subunit of …
Beta-amyloid monomers are neuroprotective
2009
The 42-aa-long β-amyloid protein—Aβ1-42—is thought to play a central role in the pathogenesis of Alzheimer's disease (AD) (Walsh and Selkoe, 2007). Data from AD brain (Shankar et al., 2008), transgenic APP (amyloid precursor protein)-overexpressing mice (Lesné et al., 2006), and neuronal cultures treated with synthetic Aβ peptides (Lambert et al., 1998) indicate that self-association of Aβ1-42monomers into soluble oligomers is required for neurotoxicity. The function of monomeric Aβ1-42is unknown. The evidence that Aβ1-42is present in the brain and CSF of normal individuals suggests that the peptide is physiologically active (Shoji, 2002). Here we show that synthetic Aβ1-42monomers support …
Implications of alpha- and beta-secretase expression and function in Alzheimer's disease
2020
Abstract There has been intense debate in the field about the extent to which processing of the amyloid precursor protein contributes to pathogenesis of Alzheimer's disease. Early publications succeeding in the identification of the main component of senile plaques—the amyloid-beta (A-beta) peptide—strictly argued for a constitutive contribution of A-beta to disease initiation and progression. This led to development of the amyloid hypothesis, which in recent years was attacked for the lack of success of clinical studies based on the respective assumption. There is evidence that the hypothesis must be revisited, but accumulation of A-beta along with aging might still be the best explanation…
Heterocyclic Scaffolds for the Treatment of Alzheimer's Disease
2016
Background: The treatment and diagnosis of Alzheimer’s Disease (AD) are two of the most urgent goals for research around the world. The cognitive decline is generally associated with the elevated levels of extracellular senile plaques, intracellular neurofibril- lary tangles (NFTs), and with a progressive shutdown of the cholinergic basal forebrain neurons transmission. Even if several key targets are under fervent investigation in the cure of AD, till now, the only approved therapeutic strategy is the treatment of symptoms by using cholinesterases inhibitors. It has been demonstrated that both acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) enzymes are not only responsible of…
The selective β1-adrenoceptor antagonist nebivolol is a potential oestrogen receptor agonist with neuroprotective abilities
2010
Background and purpose: Nebivolol, a selective β1-adrenoceptor antagonist mediating rapid vasodilating effects, is used clinically to treat hypertension. Recently, it was reported that nebivolol also acts as an oestrogen receptor (ER) agonist. To investigate the neuroprotective potential of oestrogens, we assessed the oestrogenic effects of nebivolol in several in vitro neuronal models. Experimental approach: Human neuroepithelioma SK-N-MC cells stably transfected with human ER α and β, and mouse N2A neuroblastoma cells expressing human APP695SWE[N2Aswe, stably transfected with the Swedish mutation form of the Alzheimer-associated amyloid precursor protein (APPswe, K670M/N671L)] were incu…
Selective Modulation of Aβ42 Production in Alzheimers Disease: Non-Steroidal Anti-Inflammatory Drugs and Beyond
2006
The amyloid-β (Aβ) peptides and in particular the longer, highly amyloidogenic isoform Aβ42 are believed by many to be the central disease-causing agents in Alzheimers disease (AD). Consequently, academic and pharmaceutical laboratories have focused on elucidating the mechanisms of Aβ production and developing strategies to diminish Aβ formation for treatment or prevention of AD. The most substantial advances have been made with respect to inhibitors of the γ-secretase enzyme, which catalyzes the final step in the generation of Aβ from the amyloid precursor protein (APP). Highly potent γ-secretase inhibitors which suppress production of all Aβ peptides are available today. However, due to t…