The processing of amyloid precursor protein (APP) to A␤ is an important event in the pathogenesis of Alzheimer's disease, but the physiological function of APP is not well understood. Our previous work has shown that APP processing and A␤ production are regulated by the extracellular matrix protein Reelin. In the present study, we examined whether Reelin interacts with APP, and the functional consequences of that interaction in vitro. Using coimmunoprecipitation, we found that Reelin interacted with APP through the central domain of Reelin (repeats 3-6) and the E1 extracellular domain of APP. Reelin increased cell surface levels of APP and decreased endocytosis of APP in hippocampal neurons in vitro. In vivo, Reelin levels were increased in brains of APP knock-out mice and decreased in APP-overexpressing mice. RNA interference knockdown of APP decreased neurite outgrowth in vitro and prevented Reelin from increasing neurite outgrowth. Knock-out of APP or Reelin decreased dendritic arborization in cortical neurons in vivo, and APP overexpression increased dendritic arborization. APP and Reelin have previously been shown to promote neurite outgrowth through interactions with integrins. We confirmed that APP interacted with ␣3␤1 integrin, and ␣3␤1 integrin altered APP trafficking and processing. Addition of an ␣3␤1 integrin antibody prevented APP and Reelin-induced neurite outgrowth. These findings demonstrate that Reelin interacts with APP, potentially having important effects on neurite development.

Dysglycemia, in this survey defined as impaired glucose tolerance (IGT) or type 2 diabetes, is common in patients with coronary artery disease (CAD) and associated with an unfavorable prognosis. This European survey investigated dysglycemia screening and risk factor management of patients with CAD in relation to standards of European guidelines for cardiovascular subjects. RESEARCH DESIGN AND METHODS The European Society of Cardiology's European Observational Research Programme (ESC EORP) European Action on Secondary and Primary Prevention by Intervention to Reduce Events (EUROASPIRE) V (2016-2017) included 8,261 CAD patients, aged 18-80 years, from 27 countries. If the glycemic state was unknown, patients underwent an oral glucose tolerance test (OGTT) and measurement of glycated hemoglobin A 1c. Lifestyle, risk factors, and pharmacological management were investigated. RESULTS A total of 2,452 patients (29.7%) had known diabetes. OGTT was performed in 4,440 patients with unknown glycemic state, of whom 41.1% were dysglycemic. Without the OGTT, 30% of patients with type 2 diabetes and 70% of those with IGT would not have been detected. The presence of dysglycemia almost doubled from that selfreported to the true proportion after screening. Only approximately one-third of all coronary patients had completely normal glucose metabolism. Of patients with known diabetes, 31% had been advised to attend a diabetes clinic, and only 24% attended. Only 58% of dysglycemic patients were prescribed all cardioprotective drugs, and use of sodium-glucose cotransporter 2 inhibitors (3%) or glucagon-like peptide 1 receptor agonists (1%) was small. CONCLUSIONS Urgent action is required for both screening and management of patients with CAD and dysglycemia, in the expectation of a substantial reduction in risk of further cardiovascular events and in complications of diabetes, as well as longer life expectancy.

Diabetes mellitus is a chronic disorder that affects predominantly the carbohydrate metabolism, but also the biotransformation of proteins and fat. Many intra-and extracellular metabolic mechanisms are impaired which leads to structural changes in the vascular wall and the heart muscle. This eventually causes their functional deterioration and the end result is clinical manifestation of macrovascular incidents or heart failure. People with perturbations of the glucose metabolism (impaired fasting glucose, impaired glucose tolerance and insulin resistance) are also with a higher risk of cardiovascular diseases, even before the diagnosis of diabetes. Nowadays we have a cheap, easy and non-invasive method for early diagnosis of cardiovascular disorders, way before their clinical manifestation, and that is the ultrasound methodology. The echocardiography is a valuable technique for the detection of changes in the myocardial structure and its contractility. The tissue Doppler ultrasound is a more precise method that can detect the slightest aberrations in the heart muscle function, that could not be seen with the conventional echocardiography. Subclinical atherosclerotic changes can be determined with a Doppler scan of the big arteries (carotids, renal arteries), and the subsequent calculation of their resistive index and of the intima-media thickness. There are a lot of studies in this fi eld which show that the structural and functional impairment could be diagnosed in diabetic patients without any complaints and with otherwise healthy hearts. This means that these diagnostic methods should be used in the routine clinical examination of every diabetic individual in order to predict and possibly prevent major cardiovascular events and severe heart failure.

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