Tau protein aggregation in Alzheimer's disease: An attractive target for the development of novel therapeutic agents.

Myocardial Bridging: Diagnosis, Functional Assessment, and Management: JACC State-of-the-Art Review.

Being one of the hallmarks of Alzheimer's disease, β-amyloid (Aβ) aggregates induce complicated neurotoxicity. Evidences show that the underlying mechanism of neurotoxicity involves a glutamate receptor subtype, N-methyl-D-aspartate (NMDA) receptor, an increase in intracellular calcium(II) ion loading as well as an elevation in oxidation stress. In this work, among the 35 chemical components of Chinese herbal medicines (CHMs) being screened for inhibitors of Aβ aggregation, four of them, namely albiflorin, aloeemodin, neohesperidin and physcion, were found for the first time to exhibit a potent inhibitory effect on Aβ(1-40) and Aβ(1-42) aggregation. Their neuroprotective capability on primary hippocampal neuronal cells was also investigated by MTT assay, ROS assay and intracellular calcium(II) ion concentration measurement. It was interesting to find that physcion was rather toxic to neuronal cells while albiflorin, aloeemodin and neohesperidin reduced the toxicity and ROS induced by both monomeric and oligomeric Aβ species. In addition, albiflorin was particularly powerful in maintaining the intracellular Ca(2+) concentration.

Inhibition of β-amyloid Aggregation By Albiflorin, Aloeemodin And Neohesperidin And Their Neuroprotective Effect On Primary Hippocampal Cells Against β-amyloid Induced Toxicity

Aggregation and the formation of oligomeric intermediates of amyloid-β (Aβ) at the membrane interface of neuronal cells are implicated in the cellular toxicity and pathology of Alzheimer's disease. Small molecule compounds have been shown to suppress amyloid aggregation and cellular toxicity, but often the presence of a lipid membrane negates their activity. A high-throughput screen of 1800 small molecules was performed to search for membrane active inhibitors, and 21 primary hits were discovered. Through the use of fluorescence-based assays, transmission electron microscopy, and dot blot assays, the initial 21 primary hits were narrowed down to five lead compounds. Nuclear magnetic resonance and circular dichroism experiments were used for further confirmation of amyloid inhibition at the membrane interface and to obtain insights into the secondary structure of amyloid-β, while size exclusion chromatography was used to characterize the size of Aβ species. Lastly, dye-leakage assays allowed us to understand how the addition of the five lead compounds affected amyloid-β's ability to permeate the lipid bilayer. These results provide insights into small molecules that stabilize small amyloid species in the presence of membranes for the development of tool compounds for deeper investigations of these transient species.

/pdf/high-throughput-screening-at-the-membrane-interface-reveals-4v9eiptuvl.pdf

High-Throughput Screening at the Membrane Interface Reveals Inhibitors of Amyloid-β.

Both diabetes and hyperinsulinemia are confirmed risk factors for Alzheimer's disease. Some researchers proposed that antidiabetic drugs may be used as disease-modifying therapies, such as metformin and thiazolidinediones, although more evidence was poorly supported. The aim of the current study is to investigate the role of metformin in Aβ-induced cytotoxicity and explore the underlying mechanisms. First, the experimental results show that metformin salvaged the neurons exposed to Aβ in a concentration-dependent manner with MTT and LDH assay. Further, the phosphorylation levels of JNK, ERK1/2, and p38 MAPK were measured with western blot analysis. It was investigated that Aβ increased phospho-JNK significantly but had no effect on phospho-p38 MAPK and phospho-ERK1/2. Metformin decreased hyperphosphorylated JNK induced by Aβ; however, the protection of metformin against Aβ was blocked when anisomycin, the activator of JNK, was added to the medium, indicating that metformin performed its protection against Aβ in a JNK-dependent way. In addition, it was observed that metformin protected the neurons via the suppression of apoptosis. Taken together, our findings demonstrate that metformin may have a positive effect on Aβ-induced cytotoxicity, which provides a preclinical strategy against AD for elders with diabetes.

/pdf/metformin-alleviated-ab-induced-apoptosis-via-the-ty3cz8xnxe.pdf

Metformin Alleviated Aβ-Induced Apoptosis via the Suppression of JNK MAPK Signaling Pathway in Cultured Hippocampal Neurons

Myocardial bridges are anatomical entities characterized by myocardium covering segments of coronary arteries. In some patients, the presence of a myocardial bridge is benign and is only incidentally found on autopsy. In other patients, however, myocardial bridges can lead to compression of the coronary artery during systolic contraction and delayed diastolic relaxation, resulting in myocardial ischemia. This ischemia in turn can lead to myocardial infarction, ventricular arrhythmias and sudden cardiac death. Myocardial bridges have also been linked to an increased incidence of atherosclerosis, which has been attributed to increased shear stress and the presence of vasoactive factors. Other studies however, demonstrated the protective roles of myocardial bridges. In this study, using systematic review and a meta-analytical approach we investigate the prevalence and morphology of myocardial bridges in both clinical imaging and cadaveric dissections. We also discuss the pathophysiology, clinical significance, and management of these anatomical entities. This article is protected by copyright. All rights reserved.

Myocardial bridges: A meta‐analysis

Small molecule interactions with amyloid proteins have had a huge impact in Alzheimer's disease (AD), especiallyin three specific areas: amyloid folding, metabolism and brain imaging. Amyloid plaque amelioration or preventionhave, until recently, driven drug development, and only a few drugs have been advanced for use in AD. Amyloid proteinsundergo misfolding and oligomerization via intermediates, eventually forming protease resistant amyloid fibrils. These fibrilsaccumulate to form the hallmark amyloid plaques and tangles of AD. Amyloid binding compounds can be groupedinto three categories, those that: i) prevent or reverse misfolding, ii) halt misfolding or trap intermediates, and iii) acceleratethe formation of stable and inert amyloid fibrils. Such compounds include hydralazine, glycosaminoglycans, curcumin,beta sheet breakers, catecholamines, and ATP. The versatility of amyloid binding compounds suggests that the amyloidstructure may serve as a scaffold for the future development of sensors to detect such compounds. Metabolic dysfunctionis one of the earliest pathological features of AD. In fact, AD is often referred to as type 3 diabetes due to the presenceof insulin resistance in the brain. A recent study indicates that altering metabolism improves cognitive function.While metabolic reprogramming is one therapeutic avenue for AD, it is more widely used in some cancer therapies. FDAapproved drugs such as metformin, dichloroacetic acid (DCA), and methylene blue can alter metabolism. These drugs cantherefore be potentially applied in alleviating metabolic dysfunction in AD. Brain imaging has made enormous stridesover the past decade, offering a new window to the mind. Recently, there has been remarkable development of compoundsthat have the ability to image both types of pathological amyloids: tau and amyloid beta. We have focused on thelow cost, simple to use, near infrared fluorescence (NIRF) imaging probes for amyloid beta (Aβ), with specific attentionon recent developments to further improve contrast, specificity, and sensitivity. With advances in imaging technologies,such fluorescent imaging probes will open new diagnostic avenues.

Small molecules and Alzheimer's disease: misfolding, metabolism and imaging.

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Myocardial bridges: A meta‐analysis

Small molecules and Alzheimer's disease: misfolding, metabolism and imaging.