Neuroscience
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The neuronal adaptor X11alpha interacts with the conserved -GYENPTY- sequence in the C-terminus of amyloid precursor protein (APP) or its Swedish mutation (APPswe) to inhibit Abeta40 and Abeta42 secretion. We hypothesized that the -YENP- motif essential for APP endocytosis is also essential for X11alpha-mediated effects on APP trafficking and metabolism, and that X11alpha modulates APP metabolism in both secretory and endocytic pathways. X11alpha failed to interact with the endocytic-defective APPswe mutants Y738A, N740A, or P741A, and thus did not modulate their trafficking or metabolism. ⋯ In contrast to endocytic-defective mutants, X11alpha interacted with APPswe Y743A as well as with APPswe. Thus, similar to APPswe, coexpression of X11alpha with APPswe Y743A retarded its maturation, prolonged its half-life, and inhibited APPs, Abeta40, and Abeta42 secretion. Collectively, these data suggest that by direct interaction with the APPswe -YENP- motif in the cytoplasmic tail, X11alpha modulated its trafficking and processing in both secretory and endocytic compartments, and may reduce secretion of Abeta generated in either pathway.
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Comparative Study
The proprotein convertase PC2 is involved in the maturation of prosomatostatin to somatostatin-14 but not in the somatostatin deficit in Alzheimer's disease.
A somatostatin deficit occurs in the cerebral cortex of Alzheimer's disease patients without a major loss in somatostatin-containing neurons. This deficit could be related to a reduction in the rate of proteolytic processing of peptide precursors. Since the two proprotein convertases (PC)1 and PC2 are responsible for the processing of neuropeptide precursors directed to the regulated secretory pathway, we examined whether they are involved first in the proteolytic processing of prosomatostatin in mouse and human brain and secondly in somatostatin defect associated with Alzheimer's disease. ⋯ However, the content and enzymatic activity of the PC2 mature form were similar in Alzheimer patients and controls. Therefore, the cortical somatostatin defect is not due to convertase alteration occuring during Alzheimer's disease. Further studies will be needed to assess the mechanisms involved in somatostatin deficiency in Alzheimer's disease.
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Comparative Study
Serotonergic serotonin (1A) mixed agonists/antagonists elicit large-magnitude phase shifts in hamster circadian wheel-running rhythms.
The biological clock that generates circadian rhythms in mammals is located within the suprachiasmatic nuclei at the base of the hypothalamus. The circadian clock is entrained to the daily light/dark cycle by photic information from the retina. The retinal input to the clock is inhibited by exogenously applied serotonin agonists, perhaps mimicking an endogenous inhibitory serotonergic input to the clock arriving from the midbrain raphe. ⋯ These results suggest that pharmacologically blocking raphe input to the suprachiasmatic circadian clock results in substantially larger photically induced phase advances in wheel-running rhythms. This is further evidence that raphe input to the circadian clock is probably acting to dampen the clock's response to light under certain conditions. The large-magnitude phase shifts, and temporal-activity profile seen with BMY 7378 and S 15535, suggest that compounds with this unique pharmacological profile may be beneficial in the treatment of circadian phase delays recently reported to be a complication resulting from Alzheimer's disease.
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Comparative Study
The mouse nac1 gene, encoding a cocaine-regulated Bric-a-brac Tramtrac Broad complex/Pox virus and Zinc finger protein, is regulated by AP1.
NAC1 cDNA was identified as a novel transcript induced in the nucleus accumbens from rats chronically treated with cocaine. NAC1 is a member of the Bric-a-brac Tramtrac Broad complex/Pox virus and Zinc finger family of transcription factors and has been shown by overexpression studies to prevent the development of behavioral sensitization resulting from repeated cocaine treatment. This paper reports the cloning and characterization of the corresponding gene. ⋯ Activation of immediate early genes such as c-fos and c-jun following chronic drug treatments has been well characterized. The present data describe one potential regulatory cascade involving these transcription factors and activation of NAC1. Identification of drug induced alterations in gene expression is key to understanding the types of molecular adaptations underlying addiction.
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For peripheral iron to reach the brain, it must transverse the blood-brain barrier. In order for the brain to obtain iron, transferrin receptors are present in the vascular endothelial cell to facilitate movement of transferrin bound iron into the brain parenchyma. However, a number of significant voids exist in our knowledge about transport of iron into the brain. ⋯ Blocking pinocytosis had no effect on either transferrin or iron transcytosis. These results indicate that there is both transferrin-mediated and non-transferrin-mediated transcytosis of iron and that the process is influenced by the iron status of the cells. These data have considerable implications for common neurodegenerative diseases that are associated with excess brain iron accumulation and the numerous neurological complications associated with brain iron deficiency.