NGF controls APP cleavage by downregulating APP phosphorylation at Thr668: relevance for Alzheimer's disease

NGF has been implicated in forebrain neuroprotection from amyloidogenesis and Alzheimer's disease (AD). However, the underlying molecular mechanisms are still poorly understood. Here, we investigated the role of NGF signalling in the metabolism of amyloid precursor protein (APP) in forebrain neurons using primary cultures of septal neurons and acute septo-hippocampal brain slices. In this study, we show that NGF controls the basal level of APP phosphorylation at Thr668 (T668) by downregulating the activity of the Ser/Thr kinase JNK(p54) through the Tyr kinase signalling adaptor SH2-containing sequence C (ShcC). We also found that the specific NGF receptor, Tyr kinase A (TrkA), which is known to bind to APP, fails to interact with the fraction of APP molecules phosphorylated at T668 (APPpT668). Accordingly, the amount of TrkA bound to APP is significantly reduced in the hippocampus of ShcC KO mice and of patients with AD in which elevated APPpT668 levels are detected. NGF promotes TrkA binding to APP and APP trafficking to the Golgi, where APP\u2013BACE interaction is hindered, finally resulting in reduced generation of sAPP\u3b2, CTF\u3b2 and amyloid-beta (1-42). These results demonstrate that NGF signalling directly controls basal APP phosphorylation, subcellular localization and BACE cleavage, and pave the way for novel approaches specifically targeting ShcC signalling and/or the APP\u2013TrkA interaction in AD therapy

Serine racemase: a key player in apoptosis and necrosis.

A fine balance between cell survival and cell death is required to sculpt the nervous system during development. However, an excess of cell death can occur following trauma, exposure to neurotoxins or alcohol, and some developmental and neurodegenerative diseases, such as Alzheimer's disease (AD). N-Methyl-D-aspartate receptors (NMDARs) support synaptic plasticity and survival of many neuronal populations whereas inappropriate activation may promote various forms of cell death, apoptosis, and necrosis representing the two extremes of a continuum of cell death processes both "in vitro" and "in vivo." Hence, by identifying the switches controlling pro-survival vs. apoptosis and apoptosis vs. pro-excitotoxic outcome of NMDAR stimulation, NMDAR modulators could be developed that selectively block the cell death enhancing pro-survival signaling or synaptic plasticity mediated by NMDAR. Among these modulators, a role is emerging for the enzyme serine racemase (SR) that synthesizes D-serine, a key co-agonist with glutamate at NMDAR. This review summarizes the experimental evidence from "in vitro" neuronal cultures-with special emphasis on cerebellar granule neurons (CGNs)-and "in vivo" models of neurodegeneration, where the dual role of the SR/D-serine pathway as a master regulator of apoptosis and the apoptosis-necrosis shift will be discussed

Development, validation and field application of an RNA-based growth index in juvenile plaice Pleuronectes platessa

A general mechanism relating RNA concentration and growth rate is derived from four physiological assumptions and developed into a growth index for juvenile plaice Pleuronectes platessa. The index describing instantaneous growth rates (G, day?1) in the laboratory with the lowest Akaike information criterion with small-sample bias adjustment was a function of RNA concentration (R, inline image), temperature (T, ° K), body mass (M, g) and DNA concentration (D, inline image): G = ?0 + ?RR + ?TT + ?T2T2 + ?MM + ?DD + ?RTRT. RNA concentration began to respond to changes in feeding conditions within 8 days, suggesting that the index reflects growth rate in the short-term. Furthermore, the index distinguished between rapid growth and negative growth of juvenile P. platessa measured directly in laboratory and field enclosures, respectively. An application of the RNA-based growth index at two beaches on the west coast of Scotland suggested that the growth of juvenile P. platessa varies considerably in space and time and is submaximum in late summer

HPV-associated lung cancers: An international pooled analysis

Human papillomavirus (HPV) is the etiologic risk factor for cervical cancer. Some studies have suggested an association with a subset of lung tumors, but the etiologic link has not been firmly established. We performed an international pooled analysis of crosssectional studies (27 datasets, n = 3249 patients) to evaluate HPV DNA prevalence in lung cancer and to investigate viral presence according to clinical and demographic characteristics. HPV16/18 were the most commonly detected, but with substantial variation in viral prevalence between geographic regions. The highest prevalence of HPV16/18 was observed in South and Central America, followed by Asia, North America and Europe (adjusted prevalence rates = 22, 5, 4 and 3%, respectively). Higher HPV16 prevalence was noted in each geographic region compared with HPV18, except in North America. HPV16/18-positive lung cancer was less likely observed among White race (adjusted odds ratio [OR] = 0.33, 95% confidence interval [CI] = 0.12-0.90), whereas no associations were observed with gender, smoking history, age, histology or stage. Comparisons between tumor and normal lung tissue show that HPV was more likely to be present in lung cancer rather than normal lung tissues (OR = 3.86, 95% CI = 2.87-5.19). Among a subset of patients with HPV16-positive tumors, integration was primarily among female patients (93%, 13/14), while the physical status in male cases (N = 14) was inconsistent. Our findings confirm that HPV DNA is present in a small fraction of lung tumors, with large geographic variations. Further comprehensive analysis is needed to assess whether this association reflects a causal relationship. © The Author 2014. Published by Oxford University Press. All rights reserved