Inhibition of ␥-secretase, one of the enzymes responsible for the cleavage of the amyloid precursor protein (APP) to produce the pathogenic -amyloid (A) peptides, is an attractive approach to the treatment of Alzheimer disease. In addition to APP, however, several other ␥-secretase substrates have been identified (e.g. Notch), and altered processing of these substrates by ␥-secretase inhibitors could lead to unintended biological consequences. To study the in vivo consequences of ␥-secretase inhibition, the ␥-secretase inhibitor LY-411,575 was administered to C57BL/6 and TgCRND8 APP transgenic mice for 15 days. Although most tissues were unaffected, doses of LY-411,575 that inhibited A production had marked effects on lymphocyte development and on the intestine. LY-411,575 decreased overall thymic cellularity and impaired intrathymic differentiation at the CD4 ؊ CD8 ؊ CD44 ؉ CD25 ؉ precursor stage. No effects on peripheral T cell populations were noted following LY-411,575 treatment, but evidence for the altered maturation of peripheral B cells was observed. In the intestine, LY-411,575 treatment increased goblet cell number and drastically altered tissue morphology. These effects of LY-411,575 were not seen in mice that were administered LY-D, a diastereoisomer of LY-411,575, which is a very weak ␥-secretase inhibitor. These studies show that inhibition of ␥-secretase has the expected benefit of reducing A in a murine model of Alzheimer disease but has potentially undesirable biological effects as well, most likely because of the inhibition of Notch processing. Alzheimer disease (AD)1 is the third most common cause of death and the leading cause of dementia in the United States (1). Although the exact cause of AD is still unknown, the etiology of the disease is almost certainly linked to several neuropathological hallmarks observed in the brains of AD victims, particularly extracellular neuritic amyloid plaques and intracellular neurofibrillary tangles (2-4). Although both of these neuropathological lesions probably contribute to progressive neuronal cell death in AD, the proximal lesion appears to be the amyloid plaques and their principal component, the A peptides. A large body of evidence strongly suggests that overproduction, aggregation, and/or plaque deposition of the A peptides, particularly A42, are central to the pathogenesis of AD (reviewed in Ref. 5). In fact, two recent studies of patients immunized against the A42 peptide have provided the first preliminary clinical evidence that A does indeed contribute to the cognitive decline in AD patients (6, 7).The A peptides are produced by the sequential proteolytic cleavage of the amyloid precursor protein (APP) by -and ␥-secretase. ␥-Secretase is a complex composed of at least four proteins, namely presenilins (presenilin 1 or -2), nicastrin, PEN-2, and APH-1 (8). Presenilin 1 and -2 have been proposed to be the novel aspartyl proteases responsible for the catalytic activity of ␥-secretase (9, 10). Because of the essential role of ␥-secretase i...
TRAIL (tumour-necrosis factor-related apoptosis ligand or Apo2L) triggers apoptosis through engagement of the death receptors TRAIL-R1 (also known as DR4) and TRAIL-R2 (DR5). Here we show that the c-Rel subunit of the transcription factor NF-kappaB induces expression of TRAIL-R1 and TRAIL-R2; conversely, a transdominant mutant of the inhibitory protein IkappaBalpha or a transactivation-deficient mutant of c-Rel reduces expression of either death receptor. Whereas NF-kappaB promotes death receptor expression, cytokine-mediated activation of the RelA subunit of NF-kappaB also increases expression of the apoptosis inhibitor, Bcl-xL, and protects cells from TRAIL. Inhibition of NF-kappaB by blocking activation of the IkappaB kinase complex reduces Bcl-x L expression and sensitizes tumour cells to TRAIL-induced apoptosis. The ability to induce death receptors or Bcl-xL may explain the dual roles of NF-kappaB as a mediator or inhibitor of cell death during immune and stress responses.
Cyclophosphamide (Cy) has been studied extensively for its immunosuppressive properties and is frequently combined with total body irradiation (TBI) as conditioning prior to HLA-identical allogeneic blood or marrow transplantation (alloBMT) in humans. Because Cy is most effective at suppressing host-versus-graft reactions when the drug is given after the transplantation (Mayumi H et al. Transplant Proc. 1986;18:363-369), we investigated whether posttransplantation Cy could prevent rejection of allogeneic marrow in mice conditioned with low-dose TBI. In a mouse model, posttransplantation Cy reduced the dose of TBI required from 500 cGy to < or = 200 cGy for the engraftment of 10 million major histocompatibility complex (MHC)-identical marrow cells in 100% of recipients. In animals conditioned with low-dose TBI and posttransplantation Cy, donor chimerism was proportional to the dose of TBI, was present in multiple hematopoietic lineages, and was associated with the indefinite survival of donor-strain skin grafts. In contrast, animals conditioned with either TBI alone or posttransplantation Cy alone failed to achieve engraftment after alloBMT and contained antidonor cytotoxic T-cells. Although <5% donor chimerism could be induced without TBI by transplanting > or = 50 million MHC-identical cells and administering posttransplantation Cy, the addition of low-dose TBI reduced the dose of donor cells required for alloengraftment and increased long-term donor chimerism to >50%. These data demonstrate that low-dose TBI and posttransplantation Cy cooperate to prevent graft rejection following the transplantation of standard doses of MHC-identical marrow cells.
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