Alpha2-macroglobulin complexes with and mediates the endocytosis of beta-amyloid peptide via cell surface low-density lipoprotein receptor-related protein

A primary histopathological feature of Alzheimer's disease is the accumulation of beta-amyloid (A beta) in the brain of afflicted individuals. However, A beta is produced continuously as a soluble protein in healthy individuals where it is detected in serum and CSF, suggesting the existence of cellular clearance mechanisms that normally prevent its accumulation and aggregation. Here, we demonstrate that A beta forms stable complexes with activated alpha2-macroglobulin (alpha2M*), a physiological ligand for the low-density lipoprotein receptor-related protein (LRP) that is abundantly expressed in the CNS. These alpha2M*/125I-A beta complexes are immunoreactive with both anti-A beta and anti-alpha2M IgG and are stable under various pH conditions, sodium dodecyl sulfate, reducing agents, and boiling. We demonstrate that alpha2M*/125I-A beta complexes can be degraded by glioblastoma cells and fibroblasts via LRP, because degradation is partially inhibited by receptor-associated protein (RAP), an antagonist of ligand interactions with LRP. In contrast, the degradation of free 125I-A beta is not inhibited by RAP and thus must be mediated via an LRP-independent pathway. These results suggest that LRP can function as a clearance receptor for A beta via a physiological ligand.     

Effects of corticotropin-releasing factor on brain serotonergic activity

The serotonergic dorsal raphe nucleus is innervated by corticotropin-releasing factor (CRF) and expresses CRF receptors, suggesting that endogenous CRF impacts on this system. The present study characterized interactions between CRF and the dorsal raphe serotonin (5-HT) system. The effects of intracerebroventricularly (i.c.v.) administered CRF on microdialysate concentrations of 5-HT in the lateral striatum of freely moving rats were determined. CRF had biphasic effects, with 0.1 and 0.3 microgram decreasing, and 3.0 micrograms increasing 5-HT dialysate concentrations. i.c.v. administration of CRF inhibited neuronal activity of the majority of dorsal raphe neurons at both low (0.3 microgram) and high (3 micrograms) doses. Likewise, intraraphe administration of CRF (0.3 and 1.0 ng) had predominantly inhibitory effects on discharge rate. Together, these results suggest that CRF is positioned to regulate the function of the dorsal raphe serotonergic system via actions within the cell body region. This regulation may play a role in stress-related psychiatric disorders in which 5-HT has been implicated.     

Effects of chronic ethanol consumption and withdrawal on the neuroactive steroid 3alpha-hydroxy-5alpha-pregnan-20-one in male and female rats

Prolonged alcohol (ethanol) consumption leads to the development of alcohol tolerance and cross-tolerance to some benzodiazepines and barbiturates. In contrast, rats undergoing alcohol withdrawal are sensitized to the anticonvulsant effects of the endogenous GABA(A) receptor modulator, 3alpha-hydroxy-5alpha-pregnan-20-one (3alpha,5alpha-THP). Alterations in endogenous, cerebral cortical levels of 3alpha,5alpha-THP during alcohol withdrawal could contribute to the observed sensitization to 3alpha,5alpha-THP. Therefore, this study investigated plasma and brain levels of 3alpha,5alpha-THP, progesterone, and corticosterone during alcohol dependence and withdrawal in the rat. Plasma corticosterone, progesterone (a precursor of 3alpha,5alpha-THP) and 3alpha,5alpha-THP levels were unchanged in alcohol-dependent animals. Cerebral cortical levels of 3alpha,5alpha-THP decreased in dependent male animals, but not in dependent female rats. During alcohol withdrawal, plasma corticosterone and progesterone levels increased in male, but not female rats. However, neither plasma nor cerebral cortical 3alpha,5alpha-THP levels were altered from control levels in male or female rats during alcohol withdrawal. Plasma and brain levels of 3alpha,5alpha-THP were markedly higher in female compared with male rats. Cerebral cortical levels of 3alpha,5alpha-THP during the diestrus phase of the estrus cycle were approximately 4 to 6 ng/g, a concentration that may approach physiological relevance. These findings suggest that sensitization to 3alpha,5alpha-THP during alcohol withdrawal is not mediated by elevations in brain levels of endogenous 3alpha,5alpha-THP in male or female rats. However, elevations in circulating corticosterone and progesterone levels during ethanol withdrawal in male rats may underlie gender differences in allopregnanolone sensitivity during ethanol withdrawal.     

Immunocytochemical investigation on dysplastic human tissue from epileptic patients

In this report we describe three patients with developmental cortical abnormalities (generally referred as cortical dysplasia), revealed by MRI and operated on for intractable epilepsy. Tissue, removed for strictly therapeutic reasons, was defined as the epileptogenic area by electroclinical data and stereo EEG (SEEG) recordings. Tissue samples were processed initially for histology, and selected sections were further processed for immunocytochemical investigation in order to determine whether the region of cortical dysplasia was co-extensive with the epileptogenic area. In two patients with nodular heterotopia, disorganized aggregates of neurons (as revealed by neuronal cytoskeletal markers) were found within the nodules. Both pyramidal and local circuit neurons were present in the nodules, but no reactive gliosis was present. When nodules reached the cortex, the cortical layers were disrupted. In the patient with localized cortical dysplasia, a complete disorganization of the cortical lamination was found, and numerous neurons were also present in the white matter. Disoriented pyramidal neurons weakly labelled with cytoskeletal neuronal markers were also present but no cytomegalic cells were found. One of the patients with nodular heterotopia underwent only partial resection of both the 'epileptogenic area' and of the lesion; this patient still presents with seizures. The other patient with nodular heterotopia is seizure-free after a complete lesionectomy and excision of the epileptogenic area. The third patient, with focal cortical dysplasia, had two surgeries; she became seizure-free only after the excision of the epileptogenic area detected by SEEG recording. The present data suggest that the dysplastic areas identified by MRI should not be considered as the only place of origin of the ictal discharges. From the neuropathological point of view, the focal cortical dysplasia can be considered as a pure form of migrational disorder. However, the presence of large aggregates of neurons interspersed within the white matter, in the subcortical nodular heterotopia, suggests that a defect of neuronal migration could be associated with an exuberant production of neuroblasts and/or a disruption of mechanisms for naturally occurring cell death.     

Role of p53 gene in colorectal neoplasms

A prospective study on the role of the p53 gene in sporadic colorectal neoplasms is presented and the level of mutant p53 protein was measured in the tissue removed during colonoscopy from: patients previously operated for colorectal malignant neoplasms, patients with active neoplasms, first degree relatives and during regular checks. 72% of patients with an active tumour showed a positive p53 and 38% in follow-up checks. Longer follow-up periods and a major number of patients are necessary to assess the prognostic importance of the p53 protein.     

The self-fulfilling prophecy in close relationships: rejection sensitivity and rejection by romantic partners

The authors hypothesized a self-fulfilling prophecy wherein rejection expectancies lead people to behave in ways that elicit rejection from their dating partners. The hypothesis was tested in 2 studies of conflict in couples: (a) a longitudinal field study where couples provided daily-diary reports and (b) a lab study involving behavioral observations. Results from the field study showed that high rejection-sensitive (HRS) people's relationships were more likely to break up than those of low rejection-sensitive (LRS) people. Conflict processes that contribute to relationship erosion were revealed for HRS women but not for HRS men. Following naturally occurring relationship conflicts, HRS women's partners were more rejecting than were LRS women's partners. The lab study showed that HRS women's negative behavior during conflictual discussions helped explain their partners' more rejecting postconflict responses.     

Photoaffinity labeling of DNA polymerase from Thermus thermophilus and DNA template by photoreactive analogs of dCTP

The aim of this study was to evaluate the influence of nicotine on the daily rhythms of heart rate, body temperature and locomotor activity in unrestrained rats by use of implanted radiotelemetry transmitters. The study was divided into three seven-day periods: a control period, a treatment period and a recovery period. The control period was used for baseline measurement of heart rate, body temperature and locomotor activity. During the treatment period three rats received nicotine (1 mg kg(-1), s.c.) at 0900 h. Three rats received saline under the same experimental conditions. Heart rate, body temperature and locomotor activity were continuously monitored and plotted every 10 min. During the three periods a power spectrum analysis was used to determine the dominant period of rhythmicity. If daily rhythms of heart rate, body temperature and locomotor activity were detected, the characteristics of these rhythms, i.e. the mesors, amplitudes and acrophases, were determined by cosinor analysis, expressed as means +/- s.e.m. and compared by analysis of variance. Nicotine did not suppress daily rhythmicity but induced decreases of amplitudes and phase-advances of acrophases for heart rate, body temperature and locomotor activity. These perturbations might result from the effects of nicotine on the suprachiasmatic nucleus, the hypothalamic clock that co-ordinates biological rhythms.