Search results for "amyloid beta"
showing 10 items of 191 documents
Insensitivity to Aβ42-lowering Nonsteroidal Anti-inflammatory Drugs and γ-Secretase Inhibitors Is Common among Aggressive Presenilin-1 Mutations
2007
Abeta42-lowering nonsteroidal anti-inflammatory drugs (NSAIDs) constitute the founding members of a new class of gamma-secretase modulators that avoid side effects of pan-gamma-secretase inhibitors on NOTCH processing and function, holding promise as potential disease-modifying agents for Alzheimer disease (AD). These modulators are active in cell-free gamma-secretase assays indicating that they directly target the gamma-secretase complex. Additional support for this hypothesis was provided by the observation that certain mutations in presenilin-1 (PS1) associated with early-onset familial AD (FAD) change the cellular drug response to Abeta42-lowering NSAIDs. Of particular interest is the P…
Regulation of the alpha-secretase ADAM10 by its prodomain and proprotein convertases.
2001
SPECIFIC AIMSTo identify the proprotein convertases responsible for maturation of the α-secretase ADAM10, we investigated the influence of PC7 and furin on ADAM10 processing and the resulting effect on amyloid precursor protein cleavage. We also examined the functional role of the ADAM10 prodomain by coexpression of a prodomain-deleted ADAM10 mutant together with its prodomain in trans.PRINCIPAL FINDINGS1. ADAM10 is proteolytically processed by PC7 and furinThe disintegrin metalloproteinase ADAM10 possesses α-secretase activity as well as a potential proprotein convertase recognition sequence (RKKR) after its prodomain. By amino-terminal sequencing of ADAM10 purified from bovine kidney plas…
The deubiquitinase USP11 is a versatile and conserved regulator of autophagy
2021
Autophagy is a major cellular quality control system responsible for the degradation of proteins and organelles in response to stress and damage to maintain homeostasis. Ubiquitination of autophagy-related proteins or regulatory components is important for the precise control of autophagy pathways. Here, we show that the deubiquitinase ubiquitin-specific protease 11 (USP11) restricts autophagy and that KO of USP11 in mammalian cells results in elevated autophagic flux. We also demonstrate that depletion of the USP11 homolog H34C03.2 in Caenorhabditis elegans triggers hyperactivation of autophagy and protects the animals against human amyloid-β peptide 42 aggregation-induced paralysis. USP11…
Experimental Inhibition of Fibrillogenesis and Neurotoxicity by amyloid-beta (Aβ) and Other Disease-Related Peptides/Proteins by Plant Extracts and H…
2012
Amyloid-β (Aβ) fibrillogenesis and associated cyto/neurotoxicity are major pathological events and hallmarks in diseases such as Alzheimer’s disease (AD). The understanding of Aβ molecular pathogenesis is currently a pharmacological target for rational drug design and discovery based on reduction of Aβ generation, inhibition of Aβ fibrillogenesis and aggregation, enhancement of Aβ clearance and amelioration of associated cytotoxicity. Molecular mechanisms for other amyloidoses, such as transthyretin amyloidosis, AL-amyloidosis, as well as α-synuclein and prion protein are also pharmacological targets for current drug therapy, design and discovery. We report on natural herbal compounds and e…
The Role of the anti-amyloidogenic secretase ADAM10 in shedding the APP-like proteins.
2011
ADAM10 (A disintegrin and metalloproteinase 10) has been demonstrated as an enzyme with protective properties in Alzheimer's disease: in mouse models it not only lowered generation of toxic A-beta peptides and formation of senile plaques but also alleviated learning deficits and enhanced synaptic density. This is due to cleavage of the amyloid precursor protein (APP) within its A-beta stretch and to the release of the extracellular domain of APP with neuroprotective function. Aside from cleaving APP, ADAM10 has been linked to over 40 putative substrates at least in cell culture. These substrates are connected with important cellular functions such as cell migration, stress response and tran…
Oxidative Stress And Ubiquitin Ligases: Their Involvement In Alzheimer’s Disease Pathophysiology
2015
Oxidative stress is a major hallmark in Alzheimer’s Disease. We showed that amyloid beta (Aβ 1-42 ), induces mitochondrial oxidative stress. We focused on dysregulations of ubiquitin ligases in Alzheimer’s and their relation to oxidative stress. The anaphase-promoting complex/cyclosome (APC/C)-Cdh1 ubiquitin ligase has a role as cell cycle regulator in proliferating cells and, recently another role in the regulation the degradation of key glycolytic enzyme 6-phosphofructo-2-kinase/fructose-2, 6-bisphosphatase-3 has been found (Almeida et al., 2012). Herrero-Mendez et al. observed in 2009 that inhibition of Cdh1 leads to an upregulation of Pfkfb3 in neurons and that this results in the activ…
Hsp60 Protects against Amyloid β Oligomer Synaptic Toxicity via Modification of Toxic Oligomer Conformation
2019
Alzheimer's disease (AD) is the leading cause of dementia worldwide. While the etiology of AD remains uncertain, neurotoxic effects of amyloid beta oligomers (Aβo) on synaptic function, a well-established early event in AD, is an attractive area for the development of novel strategies to modify or cease the disease's progression. In this work, we tested the protective action of the mitochondrial chaperone Hsp60 against Aβo neurotoxicity, by determining the direct effect of Hsp60 in changing Aβo toxic conformations and thus reducing their dysfunctional synaptic binding and consequent suppression of long-term potentiation. Our data suggest that Hsp60 has a direct impact on Aβo, resulting in a…
Photo-inhibition of Ab fibrillation mediated by a newly designed fluorinated oxadiazole
2015
Uncontrolled aggregation of amyloid beta peptide (A?) is the main cause of Alzheimer's Disease. Therapeutic approaches of intervention in amyloid diseases include the use of small molecules able to stabilize the soluble A? conformation, or to redirect the amyloidogenic pathway towards non-toxic and non-fibrillar states. Fluorometric measurements revealed that the 3-(4'-trifluoromethylphenyl)-5-(4'-methoxyphenyl)-1,2,4-oxadiazole, when irradiated, is able to interact with monomeric A? peptide readdressing the aggregation pathway toward the formation of amorphous aggregates as evidenced by means of CD, AFM, and SAXS measurements. We hypothesize that this compound, under radiation, forms a rea…
Melatonin stimulates the nonamyloidogenic processing ofβAPP through the positive transcriptional regulation of ADAM10 and ADAM17
2014
Melatonin controls many physiological functions including regulation of the circadian rhythm and clearance of free radicals and neuroprotection. Importantly, melatonin levels strongly decrease as we age and patients with Alzheimer's disease (AD) display lower melatonin than age-matched controls. Several studies have reported that melatonin can reduce aggregation and toxicity of amyloid-β peptides that are produced from the β-amyloid precursor protein (βAPP). However, whether melatonin can directly regulate the βAPP-cleaving proteases ('secretases') has not been investigated so far. In this study, we establish that melatonin stimulates the α-secretase cleavage of βAPP in cultured neuronal an…
Selection of Membrane RNA Aptamers to Amyloid Beta Peptide: Implications for Exosome-Based Antioxidant Strategies
2019
The distribution of amyloid beta peptide 42 (Aβ42) between model exosomal membranes and a buffer solution was measured. The model membranes contained liquid-ordered regions or phosphatidylserine. Results demonstrated that up to ca. 20% of amyloid peptide, generated in the plasma (or intracellular) membrane as a result of proteolytic cleavage of amyloid precursor proteins by β- and γ-secretases, can stay within the membrane milieu. The selection of RNA aptamers that bind to Aβ42 incorporated into phosphatidylserine-containing liposomal membranes was performed using the selection-amplification (SELEX) method. After eight selection cycles, the pool of RNA aptamers was isol…