Search results for "AMYLOID"

Alpha-secretase activation--an approach to Alzheimer's disease therapy.

2006

The nonamyloidogenic pathway of processing the amyloid precursor protein (APP) involves the cleavage within the amyloid-beta peptide sequence, and thus precludes amyloid-beta formation. The identification of a member of the disintegrin and metalloproteinase family, ADAM10, as an alpha-secretase that prevents plaque formation and hippocampal deficits in vivo gave us the possibility to examine the alpha-secretase as a potential target for the therapy of Alzheimer's disease. Within the priority program Cellular Mechanisms of Alzheimer's Disease, we investigated several approaches to stimulate the alpha-secretase pathway. Two protein convertases were found to be responsible for the removal of t…

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…

The Non-Amyloidogenic Pathway: Structure and Function of α-Secretases

2006

The amyloid cascade hypothesis is the most accepted explanation for the pathogenesis of Alzheimer’s disease (AD). APP is the precursor of the amyloid β peptide (Aβ), the principal proteinaceous component of amyloid plaques in brains of Alzheimer’s disease patients. Proteolytic cleavage of APP by the α-secretase within the Aβ sequence precludes formation of amyloidogenic peptides and leads to a release of soluble APPsα which has neuroprotective properties. In several studies, a decreased amount of APPsα in the cerebrospinal fluid of AD patients has been observed. Three members of the ADAM family (a disintegrin and metalloproteinase) ADAM-10, ADAM-17 (TACE) and ADAM-9 have been proposed as α-…

P3‐271: Presenilin‐1 (PS1) and amyloid precursor protein (APP) mutations present in mouse models of Alzheimer's disease in their response to γ‐secret…

2009

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…

Highly tunable protein microspheres for drug delivery

2019

It is well-known that protein amyloid aggregation has profound implications in several neurodegenerative diseases. In contrast, a natural role for amyloid structures as protection, adhesion and storage materials in living system is also reported, promoting protein aggregates as an interesting platform for the design of multifunctional biomaterials. Among the broad range of different amyloid structures protein particulates deserve special attention; they are spherical protein aggregates with radius ranging from hundreds of nm to few um which are readily formed in solution at pHs values near the isoelectric point of the protein they are made of. Interestingly, particulate appears to be a gene…

Is Oxidative Stress the Link Between Cerebral Small Vessel Disease, Sleep Disruption, and Oligodendrocyte Dysfunction in the Onset of Alzheimer’s Dis…

2021

Oxidative stress is an early occurrence in the development of Alzheimer’s disease (AD) and one of its proposed etiologic hypotheses. There is sufficient experimental evidence supporting the theory that impaired antioxidant enzymatic activity and increased formation of reactive oxygen species (ROS) take place in this disease. However, the antioxidant treatments fail to stop its advancement. Its multifactorial condition and the diverse toxicological cascades that can be initiated by ROS could possibly explain this failure. Recently, it has been suggested that cerebral small vessel disease (CSVD) contributes to the onset of AD. Oxidative stress is a central hallmark of CSVD and is depicted as …

Effectiveness and Safety of Oral Anticoagulants in Cardiac Amyloidosis: Lights and Shadows

2022

Cardiac amyloidosis (CA) is an infiltrative cardiomyopathy characterized by extracellular deposition of mis-folded proteins called amyloid. Cardiac complications of CA are several: heart failure, aortic valve stenosis, thromboembolism, conduction disorders, atrial fibrillation, and ventricular arrhythmias. Atrial dysfunction is common in CA patients. Several evidences suggest to anticoagulated patients with CA in atrial fibrillation independently from CHA2DS2VaSC score. Considering the high thromboembolic risk in CA patients, anticoagulant therapy should be considered also in CA patients in sinus rhythm, when the atria are enlarged and dysfunctional, and the bleeding risk is low. Unfortunat…

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…

Thioflavin T Promotes Aβ(1−40) Amyloid Fibrils Formation

2015

Fibrillogenesis of the small peptide Aβ(1-40) is considered to be the hallmark of Alzheimer's disease. Some evidence indicates small oligomers, rather than mature fibrils, as the key cytotoxic agents. The fluorescent dye Thioflavin T (ThT) is often used to detect amyloid deposits in both in vivo and in vitro experiments, and it is used to study kinetic measurements, under the fundamental hypothesis that this probe does not influence the aggregation processes. We report experimental data showing that ThT may promote the Aβ(1-40) peptide amyloid aggregation changing solvent-peptide interactions and stabilizing more ordered β-like conformation. This finding has a two-fold importance: It is a f…