Recent visual laterality studies have included trials in which critical stimulus information is presented simultaneously in both visual half-fields and, thereby, simultaneously to both cerebral hemispheres. To investigate interhemispheric interaction, researchers compare performance on bilateral redundant trials with performance on unilateral trials in which a single copy of the target is presented to one hemisphere or the other. The authors used the identification of nonword letter trigrams to examine the relationship between unilateral and bilateral performance when the 2 types of trials were equated for the number of locations stimulated (Experiment 1) and the number of redundant copies of the target (Experiment 2). Results suggest that when the number of stimulated locations is held constant, each of 2 copies of a target stimulus can be processed with the same efficiency and the same strategy as it would have been had it been the only copy.

Caspase-3 activity increased dramatically in cytosolic extracts of rat cerebellar granule cells exposed to apoptotic conditions (basal medium Eagle (BME) containing 5 mM K+ without serum) when assayed with Ac-DEVD-amc, but not with Ac-YVAD-afc, a preferred substrate for caspase-1. This provided a basis to examine relationships between enzyme activity and cell viability for purposes of selecting an optimal time for comparing neuroprotective agents or strategies. Exposure of neurons to an apoptotic medium containing 5 mM K+ in absence of serum led to a rapid 5- to 10-fold increase in caspase-3 within 2-4 hr but without significant cell loss, or morphological alterations. Exposure to apoptotic medium followed by replacement with maintenance medium containing 25 mM K+ and serum led to a rapid fall in caspase-3 and prevention of cell death. This strategy was not effective after 13 hr exposure despite a large fall in enzyme activity. These temporal changes infer systems for rapid enzyme turnover and/or activation of cytoplasmic components linked to later DNA degradation. The effects of cycloheximide point to requirements for protein synthesis, and those of Glu exclude a caspase-3 dependent pathway for necrotic cell damage. Brief treatment with 10 microM LIGA20, an anti-necrotic agent, also attenuated cell loss and caspase-3 activity, indicating a broad spectrum of neuroprotection. Rapid and long-lasting effects, together with its biophysical properties, suggest that this semisynthetic ganglioside acted upstream at or near a membrane site. As such, gangliosides provide useful agents to further probe pathways relevant to neuronal death in culture.

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Secretases are named for enzymes processing amyloid precursor protein (APP), a prototypic type-1 membrane protein. This led directly to discovery of novel Aspartyl proteases (beta-secretases or BACE), a tetramer complex gamma-secretase (gamma-SC) containing presenilins, nicastrin, aph-1 and pen-2, and a new role for metalloprotease(s) of the ADAM family as a alpha-secretases. Recent advances in defining pathways that mediate endosomal-lysosomal-autophagic-exosomal trafficking now provide targets for new drugs to attenuate abnormal production of fibril forming products characteristic of AD. A key to success includes not only characterization of relevant secretases but mechanisms for sorting and transport of key metabolites to abnormal vesicles or sites for assembly of fibrils. New developments we highlight include an important role for an 'early recycling endosome' coated in retromer complex containing lipoprotein receptor LRP-II (SorLA) for switching APP to a non-amyloidogenic pathway for alpha-secretases processing, or to shuttle APP to a 'late endosome compartment' to form Abeta or AICD. LRP11 (SorLA) is of particular importance since it decreases in sporadic AD whose etiology otherwise is unknown.

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Microinjection of the C-fragment (also called beta-endorphin), which is amino acid sequence 61-91 of the endogenous pituitary hormone, beta-lipotropin (beta-LPH), in the periaqueductal gray of the rat resulted in profound sedation and catalepsy, while microinjection of smaller fragments-that is, methionine-enkephalin [sequence beta-LPH-(61-65)] and its related pentapeptide, leucine enkephalin, and alpha-endorphin [sequence beta-LPH-(61-76)] resulted in attenuated forms of this behavior. This indicates that the C-fragment is an important neuromodulator of the central nervous system. The similarity of this behavior to that seen after systemic administration to experimental animals of exogenous neuroleptics suggests that a disturbance in the bioavailability of this neuropeptide to receptor sites in brain-perhaps due to lack of enzymatic cleavage from the circulating parent hormone, beta-lipotropin--may be an etiological factor in those psychopathological states for which the exogenous neuroleptics exert an ameliorative influence.

Myelin basic protein, purified from bovine spinal cord, is cleaved by a purified bovine brain acid proteinase to yield three peptide fragments which were purified by gel filtration procedures combined with preparative gel electrophoresis. The purity of the fragments was established by end group analysis, amino acid analysis, polyacrylamide disc gel electrophoresis, and by their encephalitogenic activity. Chemical and biological characterization shows that one'peptide, (peptide 11), originates from the N-terminal end of the basic protein and contains residues 1-43; a second peptide, (peptide I), contains residues 44-89 and a third peptide (peptide III), originates from the C-terminal region with an N-terminal phenylalanine, residue 90, through arginine, residue 170, of the basic protein. The combined amino acid composition of the three fragments account for the amino acid content of the basic protein. The structure of the three peptides demonstrates that the purified brain acid proteinase selectively cleaves the two phenylalanine-phenylalanine linkages formed between residues 43-44 and 89-90 of the basic protein molecule. This study shows that cathepsin D could be the endogenous enzyme responsible for the breakdown of basic protein to form smaller encephalitogenic fragments, some of which are known to be present in crude tissue extracts.It was established in previous studies that most myelin protein components are subject to turnover [l]. Basic protein of myelin is of particular interest because it is known to induce an autoimmune disease associated with demyelination, experimental allergic encephalomyelitis. Previously, Einstein et af. [2] showed that basic protein can be cleaved by acid proteinase to form smaller encephalitogenic fragments, but the composition of these, and the nature of the susceptible bonds cleaved, have never been established. Indeed, early studies on the isolation and structure of basic protein were accompanied by autolysis during extraction, leading to the fortuitous isolation of polypeptide fragments, some of which were encephalitogenic in a particular species [3-51. Therefore, it is of some interest to establish the exact mechanism of basic protein breakdown using a known intracellular enzyme, since this may have some bearing on demyelinating processes in experimental disease and, in addition, provide some insight into the general mechanism of protein turnover in brain. A limited and specific degradation of basic protein could lead to the production of smaller (diffusible) peptides capable of interaction at the immunological sites related to autoimmune phenomena. The present work was designed to determine the nature of the peptide bonds split by the action of brain cathepsin D, as well as the structure and biological activity of the resultant peptides based on the known structure of bovine basic protein [6]. In other tissues, Coffey and de Duve [7] showed that catheptic activity of lysosomes appear to play a rate-limiting role in the pathways of protein breakdown. Thus, studies on the...