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␤-Amyloid protein is thought to underlie the neurodegeneration associated with Alzheimer's disease by inducing Ca 2؉ -dependent apoptosis. Elevated neuronal expression of the proinflammatory cytokine interleukin-1␤ is an additional feature of neurodegeneration, and in this study we demonstrate that interleukin-1␤ modulates the effects of ␤-amyloid on Ca 2؉ homeostasis in the rat cortex. ␤-Amyloid-(1-40) (1 M) caused a significant increase in 45 Ca 2؉ influx into rat cortical synaptosomes via activation of L-and N-type voltage-dependent Ca 2؉ channels and also increased the amplitude of N-and P-type Ca 2؉ channel currents recorded from cultured cortical neurons. In contrast, interleukin-1␤ (5 ng/ml) reduced the 45 Ca 2؉ influx into cortical synaptosomes and inhibited Ca 2؉ channel activity in cultured cortical neurons. Furthermore, the stimulatory effects of ␤-amyloid protein on Ca 2؉ influx were blocked following exposure to interleukin-1␤, suggesting that interleukin-1␤ may govern neuronal responses to ␤-amyloid by regulating Ca 2؉ homeostasis.␤-Amyloid (A␤-(1-40)) 1 is a peptide fragment derived from proteolytic processing of ␤-amyloid precursor protein (␤APP) (1), which accumulates as an insoluble extracellular deposit around neurons, giving rise to the senile plaques associated with Alzheimer's disease (AD) (2). Increased neuronal expression of the proinflammatory cytokine interleukin-1␤ (IL-1␤) is an additional neuropathological hallmark of AD (3), and inflammatory mediators such as IL-1␤ have been proposed to contribute to the development of amyloid plaques (4). Several reports describe an interaction between IL-1␤ and A␤ at the processing level; IL-1-immunoreactive microglia are prominent components of amyloid plaques in AD (4), and ␤-amyloid promotes release of IL-1␤ by the glial cells that surround senile plaques (5). In turn, IL-1␤ increases ␤APP mRNA expression (6) and promotes processing of ␤APP to liberate A␤ peptide fragments (7). Thus a chain of events involving IL-1␤ and A␤ is involved in plaque formation; however, the nature of the interaction between IL-1␤ and A␤ at a physiological level is poorly understood. Neuronal apoptosis is the suspected causative factor of neurodegeneration in AD, and A␤ fragments have been shown to promote apoptosis in vitro in human-derived neurotypic cells (8) and cultured neurons (9). The mechanism underlying A␤-induced apoptosis is thought to involve disregulation of Ca 2ϩ homeostasis (10). In the C6 glial cell line, expression of the Ca 2ϩ -binding protein calbindin was found to suppress A␤-induced apoptosis (11), providing evidence for the involvement of Ca 2ϩ fluxes in A␤-induced apoptosis. In this study we report that A␤-(1-40) (i) promotes a stimulation of 45 Ca 2ϩ influx into cortical synaptosomes via activation of L-and N-type voltagedependent Ca 2ϩ channels (VDCCs) and (ii) increases the amplitude of N-and P-type VDCC current in cultured cortical neurons. Furthermore, the A␤-(1-40)-induced increase in Ca 2ϩ influx is blocked by the proinflammatory mediato...

Male rats given 250 mug oestradiol benzoate by subcutaneous injection on Day 4 of postnatal life showed a marked delay in the onset of the pubertal increase in the weight of the testes and seminal vesicles and in spermatogenesis but not a complete failure of sexual development. The increase in plasma testosterone concentration at puberty was also delayed in oestrogen-treated males but the eventual increase in seminal vesicle weight was closely related in time to the delayed increase in plasma testosterone concentration. Both plasma LH and FSH concentrations were reduced for about 10 days after oestrogen administration as compared to control values. After 22 days of age, plasma LH concentration did not differ significantly from the control values. The plasma FSH concentration of the oestrogen-treated males showed a delayed rise to values equal to or higher than those of controls of the same age. The delayed rise in plasma FSH concentration in the oestrogen treated males preceded the delayed rise in plasma testosterone in these animals. The decrease in plasma FSH concentration from the high prepubertal values to the lower values in adults occurred at different ages in the control and in oestrogen-treated rats but in both groups the decrease occurred as plasma testosterone levels were increasing and the first wave of spermatogenesis was reaching completion. The increase in plasma FSH concentration after castration was reduced in oestrogen-treated males during the period throughout which FSH levels in the intact animals were subnormal but the levels in oestrogen-treated males castrated after the delayed rise in FSH had occurred did not differ from control values. It is suggested that the delayed sexual maturation of male rats treated with high doses of oestrogen in the neonatal period is related principally to abnormalities in the secretion of FSH.

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