Amyloid precursor protein and amyloid beta-peptide bind to ATP synthase and regulate its activity at the surface of neural cells

Amyloid precursor protein (APP) and amyloid beta-peptide (Abeta) have been implicated in a variety of physiological and pathological processes underlying nervous system functions. APP shares many features with adhesion molecules in that it is involved in neurite outgrowth, neuronal survival and synaptic plasticity. It is, thus, of interest to identify binding partners of APP that influence its functions. Using biochemical cross-linking techniques we have identified ATP synthase subunit alpha as a binding partner of the extracellular domain of APP and Abeta. APP and ATP synthase colocalize at the cell surface of cultured hippocampal neurons and astrocytes. ATP synthase subunit alpha reaches the cell surface via the secretory pathway and is N-glycosylated during this process. Transfection of APP-deficient neuroblastoma cells with APP results in increased surface localization of ATP synthase subunit alpha. The extracellular domain of APP and Abeta partially inhibit the extracellular generation of ATP by the ATP synthase complex. Interestingly, the binding sequence of APP and Abeta is similar in structure to the ATP synthase-binding sequence of the inhibitor of F1 (IF(1)), a naturally occurring inhibitor of the ATP synthase complex in mitochondria. In hippocampal slices, Abeta and IF(1) similarly impair both short- and long-term potentiation via a mechanism that could be suppressed by blockade of GABAergic transmission. These observations indicate that APP and Abeta regulate extracellular ATP levels in the brain, thus suggesting a novel mechanism in Abeta-mediated Alzheimer's disease pathology.     

Novelty-induced behavioral traits correlate with numbers of brainstem noradrenergic neurons and septal cholinergic neurons in C57BL/6J mice

It is generally accepted that different brain regions regulate specific behavioral responses and that structural alterations in these regions may affect behavior. We investigated whether inter-individual variability in novelty-induced behaviors in C57BL/6J mice correlates with numbers of noradrenergic neurons in the locus coeruleus and cholinergic neurons in the septum. We found that exploration of new stimuli correlated negatively with numbers of noradrenergic neurons, whereas anxiety correlated positively with numbers of cholinergic neurons. The observed correlations suggest physiologically plausible links between structure and function and indicate that precise morphological estimates can be predictive for behavioral responses.     

Restricted localization of L1 and N-CAM at sites of contact between Schwann cells and neurites in culture

Schwann cell-axon contacts in developing and regenerating peripheral nerve in situ contain high levels of the recognition molecules L1 and N-CAM, while the molecules are not detectable at the ab-axonal cell surface of Schwann cells. To investigate whether Schwann cells, axons, or both contribute to the localization of the molecules at Schwann cell-axon contacts, a heterologous cell culture system consisting of Schwann cells from mice and neurons from chicken was investigated by immunoelectron microscopy using species-specific L1 and N-CAM antibodies. We showed that Schwann cells expressed both molecules only at sites of contact between Schwann cells and neurites and other Schwann cells. Schwann cells not in contact with other cells expressed both molecules on their entire cell surface. In contrast, neurites expressed G4, an L1-related molecule in chicken, on their entire cell surface independently of whether they were in contact with other cells or not. Thus, cultured Schwann cells localize L1 and N-CAM selectively at cell contact sites and may thereby stabilize their attachment to the neighboring cellular partners. © 1994 Wiley-Liss, Inc.     

Expression of tenascin in the developing and adult cerebellar cortex.

Since tenascin may influence neuronal cell development, we studied its expression pattern using immunocytochemistry, in situ hybridization, Northern blot analysis, and immunochemistry in the developing and adult mouse cerebellar cortex. Tenascin immunoreactivity was detectable in all layers of the developing cerebellar cortex. In the external granular layer, only the radially oriented processes of Golgi epithelial cells were immunoreactive, whereas the densely packed cell bodies were immunonegative. Tenascin was hardly detectable at contact sites between migrating granule cells and processes of Golgi epithelial cells. Axons of granule cells in the molecular layer were immunoreactive, whereas their cell bodies in the internal granular layer lacked detectable levels of tenascin. By in situ hybridization, only Golgi epithelial cells and astrocytes of the internal granular layer and prospective white matter, but not nerve cells, could be shown to synthesize detectable levels of tenascin mRNA in the developing mouse cerebellar cortex. Thus, tenascin in the cerebellar cortex seems to be a glia-derived molecule that becomes adsorbed to neuronal surfaces in a topographically restricted pattern in situ. Levels of tenascin protein and mRNA decreased significantly with increasing age. In the adult, tenascin immunoreactivity was weak and mainly restricted to the molecular layer and tenascin mRNA was confined to Golgi epithelial cells, indicative for a functional heterogeneity in differentiated cerebellar astrocytes. Quantitative immunoblot analysis revealed that the 225 and 240 kDa components of tenascin were developmentally downregulated at a faster rate than the 190 and 200 kDa components, corresponding to the faster downregulation of the 8 kilobase (kb) mRNA species compared to the 6 kb mRNA species as revealed by Northern blot analysis. These observations indicate a differentially regulated expression of the tenascin components. We hypothesize that glia-derived tenascin modifies the functional properties of nerve cell surfaces and that tenascin is involved in such different morphogenetic events as neurite growth and oligodendrocyte distribution.     

Intraoperative angiography for quality control in MIDCAB and OPCAB.

We present our initial experience with intraoperative angiographic evaluation of coronary artery bypass grafts placed on the beating heart. Thirty-three grafts were investigated in 23 patients. Transfemoral angiography was performed using an OEC 9800 mobile C-arm. Spasm of the graft and/or target vessel was present in 11 grafts, two grafts were severely stenosed requiring surgical revision. In a third case an additional bypass graft was placed due to angiography findings. There was no hospital mortality and no significant perioperative myocardial ischemic event. All patients were free of angina 6 months postoperatively. Intraoperative angiography seems to reveal valuable information in beating heart coronary surgery.     

The risk of deep venous thrombosis: a computerized epidemiologic approach

The appropriate use of prophylactic measures to prevent deep venous thrombosis is dependent on the ability of physicians to identify high-risk patients. This problem has been the subject of numerous epidemiologic reports compiled during the last several decades. Described herein is a computerized technique to condense the literature on this subject into a form better suited for practical application. This technique comprises an interactive program that calculates a patient's relative risk of developing a thrombus on the basis of a comparative evaluation of his medical profile. The computer then reports the patient's calculated relative risk along with other information that may pertain to his risk of deep venous thrombosis.     

L1 (CD171) is highly expressed in gastrointestinal stromal tumors.

The treatment strategy for mesenchymal tumors of the gastrointestinal tract is based upon typing of the tumor. Especially differential diagnosis of gastrointestinal stromal tumors (GISTs) to leiomyomas is crucial for determining radicality of surgery. L1 cell adhesion molecule (CD171) plays an essential role in tumor progression. The aim of this study was to determine expression of L1 in GISTs, smooth muscle tumors, desmoid-type fibromatosis and peripheral nerve sheath tumors (PNSTs). We retrospectively analyzed a total of 129 surgically resected primary tumors or metastases of 72 GISTs, 29 smooth muscle tumors, seven PNSTs and 21 desmoid-type fibromatosis by immunohistochemistry for c-kit, CD34, smooth muscle actin, desmin, vimentin, S-100 and L1 expression. L1 expression was detected in 53 (74%) of 72 GISTs but in none of 29 smooth muscle tumors or 21 desmoid-type fibromatosis (P<0.01 by Fisher's test). In all, four (57%) of seven peripheral nerve sheath tumors were L1-positive. Survival analysis of 55 surgically completely resected GISTs presenting without metastasis at initial diagnosis revealed no tumor-specific death among L1-negative patients (P=0.13 by log-rank test; median follow-up time 41 months) and one recurrence was observed (P=0.12). Interestingly high levels of L1 were seen in tumor vascular endothelial cells of smooth muscle tumors and PNSTs, but not in GISTs. Our data show that L1 is highly expressed in GISTs but not in smooth muscle tumors and desmoid-type fibromatosis being important differential diagnoses. The trend towards a reduced survival of L1-positive patients in this study has to be further evaluated in future trials with higher patient numbers.     

Neural recognition molecules of the immunoglobulin superfamily: signaling transducers of axon guidance and neuronal migration

Recognition molecules of the immunoglobulin superfamily have important roles in neuronal interactions during ontogeny, including migration, survival, axon guidance and synaptic targeting. Their downstream signal transduction events specify whether a cell changes its place of residence or projects axons and dendrites to targets in the brain, allowing the construction of a dynamic neural network. A wealth of recent discoveries shows that cell adhesion molecules interact with attractant and repellent guidance receptors to control growth cone and cell motility in a coordinate fashion. We focus on the best-studied subclasses, the neural cell adhesion molecule NCAM and the L1 family of adhesion molecules, which share important structural and functional features. We have chosen these paradigmatic molecules and their interactions with other recognition molecules as instructive for elucidating the mechanisms by which other recognition molecules may guide cell interactions during development or modify their function as a result of injury, learning and memory.