The prion protein as a receptor for amyloid-beta.

Increased levels of brain amyloid-beta, a secreted peptide cleavage product of amyloid precursor protein (APP), is believed to be critical in the aetiology of Alzheimer's disease. Increased amyloid-beta can cause synaptic depression, reduce the number of spine protrusions (that is, sites of synaptic contacts) and block long-term synaptic potentiation (LTP), a form of synaptic plasticity; however, the receptor through which amyloid-beta produces these synaptic perturbations has remained elusive. Laurén et al. suggested that binding between oligomeric amyloid-beta (a form of amyloid-beta thought to be most active) and the cellular prion protein (PrP(C)) is necessary for synaptic perturbations. Here we show that PrP(C) is not required for amyloid-beta-induced synaptic depression, reduction in spine density, or blockade of LTP; our results indicate that amyloid-beta-mediated synaptic defects do not require PrP(c).

Amyloid beta from axons and dendrites reduces local spine number and plasticity.

Excessive synaptic loss is thought to be one of the earliest events in Alzheimer's disease. Amyloid beta (Abeta), a peptide secreted in an activity-modulated manner by neurons, has been implicated in the pathogenesis of Alzheimer's disease by removing dendritic spines, sites of excitatory synaptic transmission. However, issues regarding the subcellular source of Abeta, as well as the mechanisms of its production and actions that lead to synaptic loss, remain poorly understood. In rat organotypic slices, we found that acute overproduction of either axonal or dendritic Abeta reduced spine density and plasticity at nearby ( approximately 5-10 mum) dendrites. The production of Abeta and its effects on spines were sensitive to blockade of action potentials or nicotinic receptors; the effects of Abeta (but not its production) were sensitive to NMDA receptor blockade. Notably, only 30-60 min blockade of Abeta overproduction permitted induction of plasticity. Our results indicate that continuous overproduction of Abeta at dendrites or axons acts locally to reduce the number and plasticity of synapses.

Nationwide volume and mortality after elective surgery in cirrhotic patients.

BACKGROUND: The outcomes after elective surgery in patients with cirrhosis have not been well studied. STUDY DESIGN: We used the Nationwide Inpatient Sample (NIS) to identify all patients undergoing elective surgery for four index operations (cholecystectomy, colectomy, abdominal aortic aneurysm repair, and coronary artery bypass grafting) from 1998 to 2005. Elixhauser comorbidity measures were used to characterize patients' disease burden. Three distinct groups were created based on severity of liver disease: patients without cirrhosis (NON-CIRR), those with cirrhosis (CIRR), and patients with cirrhosis complicated by portal hypertension (PHTN). In-hospital mortality was the primary endpoint. RESULTS: There were 22,569 patients with cirrhosis (of whom 4,214 had PHTN) who underwent 1 of the 4 index operations compared with approximately 2.8 million patients without cirrhosis having these operations. Patients with CIRR or PHTN were more likely to be women (49.5% versus 44.0%, p < 0.0001) and were less likely to be treated in a large hospital (62.8% versus 67.6%, p < 0.0001) than NON-CIRR patients. Length of hospital stay and total charges per hospitalization increased with severity of liver disease for all operations (p < 0.001, respectively). Adjusted mortality rates increased with increasing liver disease for each operation (cholecystectomy: CIRR hazard ratio [HR] 3.4, 95% CI 2.3 to 5.0; PHTN HR 12.3, 95% CI 7.6 to 19.9; colectomy: CIRR HR 3.7, 95% CI 2.6 to 5.2; PHTN HR 14.3, 95% CI 9.7 to 21.0; coronary artery bypass grafting: CIRR HR 8.0, 95% CI 5.0 to 13.0, PHTN HR 22.7, 95% CI 10.0 to 53.8; abdominal aortic aneurysm: CIRR HR 5.0, 95% CI 2.6 to 9.8, PHTN HR 7.8, 95% CI 2.3 to 26.5). CONCLUSIONS: In-hospital mortality, length of stay, and total hospital charges are significantly higher after elective surgery in cirrhotic patients, even in the absence of portal hypertension. Careful decision-making about surgery in these patients is critical as the nationwide increase in hepatitis C and cirrhosis continues.

Targeting the EphA4 receptor in the nervous system with biologically active peptides.

EphA4 is a member of the Eph family of receptor tyrosine kinases and has important functions in the developing and adult nervous system. In the adult, EphA4 is enriched in the hippocampus and cortex, two brain structures critical for learning and memory. To identify reagents that can discriminate between the many Eph receptors and selectively target EphA4, we used a phage display approach. We identified three 12-amino acid peptides that preferentially bind to EphA4. Despite lack of a common sequence motif, these peptides compete with each other for binding to EphA4 and antagonize ephrin binding and EphA4 activation at micromolar concentrations, indicating that they bind with high affinity to the ephrin-binding site. Furthermore, one of the peptides perturbs the segmental migration of EphA4-positive neural crest cells in chick trunk organotypic explants. Hence, this peptide can disrupt the physiological function of endogenous EphA4 in situ. We also identified additional peptides that bind to EphA5 and EphA7, two other receptors expressed in the nervous system. This panel of peptides may lead to the development of pharmaceuticals that differentially target Eph receptors to modulate neuronal function in specific regions of the nervous system.

Control of hippocampal dendritic spine morphology through ephrin-A3/EphA4 signaling.

Communication between glial cells and neurons is emerging as a critical parameter of synaptic function. However, the molecular mechanisms underlying the ability of glial cells to modify synaptic structure and physiology are poorly understood. Here we describe a repulsive interaction that regulates postsynaptic morphology through the EphA4 receptor tyrosine kinase and its ligand ephrin-A3. EphA4 is enriched on dendritic spines of pyramidal neurons in the adult mouse hippocampus, and ephrin-A3 is localized on astrocytic processes that envelop spines. Activation of EphA4 by ephrin-A3 was found to induce spine retraction, whereas inhibiting ephrin/EphA4 interactions distorted spine shape and organization in hippocampal slices. Furthermore, spine irregularities in pyramidal neurons from EphA4 knockout mice and in slices transfected with kinase-inactive EphA4 indicated that ephrin/EphA4 signaling is critical for spine morphology. Thus, our data support a model in which transient interactions between the ephrin-A3 ligand and the EphA4 receptor regulate the structure of excitatory synaptic connections through neuroglial cross-talk.