␥-Secretase inhibitors (GSIs) reduce amyloid-␤ (A␤) peptides but inevitably increase the ␤-C-terminal fragment (␤-CTFSubchronic dosing with either GSI rather impaired normal cognition in 3-month-old Tg2576 mice, with no inhibition on the processing of other ␥-secretase substrates, such as Notch, N-cadherin, or EphA4, in the brain. LY450139 also impaired normal cognition in wild-type mice; however, the potency was 10-fold lower than that in Tg2576 mice, indicating an APP-dependent mechanism likely with ␤-CTF accumulation. Immunofluorescence studies revealed that the ␤-CTF accumulation was localized in the presynaptic terminals of the hippocampal stratum lucidum and dentate hilus, implying an effect on presynaptic function in the mossy fibers. In contrast, both acute and subchronic dosing with GSM-2 significantly ameliorated memory deficits in Tg2576 mice and did not affect normal cognition in wild-type mice. We demonstrated a clear difference between GSI and GSM in effects on functional consequences, providing new insights into strategies for developing these drugs against Alzheimer's disease.

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Recent evidence suggests that unscheduled cell cycle activity leads to neuronal cell death. 3-Nitropropionic acid (3-NP) is an irreversible inhibitor of succinate dehydrogenase and induces cell death in both striatum and cerebral cortex. Here we analyzed the involvement of aberrant cell cycle progression in 3-NP-induced cell death in these brain regions. 3-NP reduced the level of cyclindependent kinase inhibitor p27 in striatum but not in cerebral cortex. 3-NP also induced phosphorylation of retinoblastoma protein, a marker of cell cycle progression at late G 1 phase, only in striatum. Pharmacological experiments revealed that cyclin-dependent kinase activity and N-methyl-D-aspartate (NMDA) receptor were cooperatively involved in cell death by 3-NP in striatal neurons, whereas only NMDA receptor was involved in 3-NP-induced neurotoxicity in cortical neurons. Death of striatal neurons was preceded by elevation of somatic Ca 2؉ and activation of calpain, a Ca 2؉ -dependent protease. Both striatal p27 down-regulation and cell death provoked by 3-NP were dependent on calpain activity. Moreover, transfection of p27 small interfering RNA reduced striatal cell viability. In cortical neurons, however, there was no change in somatic Ca 2؉ and calpain activity by 3-NP, and calpain inhibitors were not protective. These results suggest that 3-NP induces aberrant cell cycle progression and neuronal cell death via p27 down-regulation by calpain in striatum but not in the cerebral cortex. This is the first report for differential involvement of cell cycle reactivation in different brain regions and lightens the mechanism for region-selective vulnerability in human disease, including Huntington disease.Increasing evidence suggests that neuronal apoptosis is involved in neurodegenerative disorders (1). A greater understanding of the cellular signaling pathways that regulate neuronal apoptosis may lead to novel therapeutic targets. However, the signaling pathways are not yet fully understood.Cell cycle progression is regulated through complex events controlled through the actions of cyclin-dependent kinases (CDKs) 2 and cyclins. In addition, two classes of CDK inhibitors are involved in cell cycle arrest mechanisms (2). Interestingly, a growing body of work shows that cell cycle components are involved in neuronal apoptotic death. For instance, neuronal apoptosis is accompanied by changes in CDK activity and cyclin expression (3-7). Moreover, agents that inhibit cell cycle progression protect neuronal PC12 cells, cortical neurons, sympathetic neurons, and cerebellar granule neurons from apoptotic death (8, 9). Similarly, overexpression of CDK inhibitors or dominant-negative CDK protect neurons from death caused by loss of trophic support (10), DNA damage (11), proteosomal inhibition (12), and ischemia (13). These results suggest that cell cycle-related molecules play pivotal roles in multiple forms of neuronal cell death.3-Nitropropionic acid (3-NP) irreversibly inhibits mitochondrial enzyme succinate dehydrogenase and interrupts...

Inhibin activity was investigated using chicken granulosa cell culture medium. Chicken granulosa cells were collected individually from the largest follicle (F1 follicle) and the third largest follicle (F3 follicle) of the ovary, dispersed using enzyme and incubated in a suspension method or cultured in a monolayer method in vitro. Culture medium was assessed for follicle-stimulating hormone (FSH) inhibiting (inhibin) activity using the rat anterior pituitary cell culture method. The FSH secretion from cultured rat pituitary cells was suppressed by experimental increasing of the amounts of granulosa cell culture medium in a dose-dependent manner, though luteinizing hormone (LH) secretion was not affected in a dose-dependent manner. Inhibin activity of the granulosa cell culture medium derived from F1 follicles was higher than that from F3 follicles. These results suggest that chicken granulosa cells secrete inhibin-like substance(s) and that the F1 follicle may secrete a larger amount of inhibin than the F3 follicle.