Relevance of CD40/CD40L downstream pathways to Alzheimer's disease

The amyloid cascade hypothesis places amyloid-β at the origin of Alzheimer's disease (AD). Amyloid-β (Aβ) is the product of the sequential cleavage of the amyloid precursor protein (APP) by the enzymes β- and γ-secretases. An inflammatory component to AD has been suggested in association with CD40 (a member of the tumor necrosis factor receptor superfamily (TNFRS) and its cognate ligand CD40L. In this study, I hypothesized that the neutralization of pro-inflammatory cytokines produced downstream of CD40/CD40L interaction would reduce APP processing. I also hypothesized that blocking the binding of different adaptor proteins to CD40 by mutating its cytoplasmic tail would result in significant reduction of the APP metabolites: Aβ, sAPPβ, sAPPα, CTFβ and CTFα. ^ Treatment with CD40L of human embryonic kidney cells over-expressing both APP and CD40 (HEK/APPsw/CD40) significantly increased levels of the cytokine granulocyte macrophage colony stimulating factor (GM-CSF). Neutralizing antibodies against GM-CSF mitigated the CD40L-induced production of Aβ in these cells. Treatment of the HEK/APPsw/CD40 cells with recombinant GM-CSF significantly increased Aβ levels. GM-CSF receptor gene silencing with shRNA significantly reduced Aβ levels to below base line in non-stimulated HEK/APPsw/CD40 cells. Silencing of the GM-CSF receptor also decreased APP endocytosis (therefore reducing the availability of APP to be cleaved in the endosomes). ^ Using CD40 mutants, I show that CD40L can increase levels of Aβ(1-40), Aβ(1-42), sAPPβ, sAPPα and CTFβ independently of TRAF signaling. TRAFs had been shown to be necessary for most CD40/CD40L-dependent signaling. An increase in mature/immature APP ratio after CD40L treatment of CD40wt and CD40-mutant cells was observed, reflecting alterations in APP trafficking. CD4OL treatment of a neuroblastoma cell line over-expressing CTFβ suggested that CD40L affected γ-secretase activity. Inhibition of γ-secretase activity significantly reduced sAPPβ levels in the CD40L treated HEK/APPsw CD40wt and the CD40-mutant cells. The latter suggests CD40/CD40L interaction primarily acts on γ-secretase and affects β-secretase via a positive feedback mechanism. ^ Taken together, the results of this dissertation suggest that GM-CSF operates downstream of CD40/CD40L interaction and that GM-CSF modulates Aβ production by influencing APP trafficking. Moreover, the data presented suggest that CD40/CD40L interaction can modulate APP processing via a mechanism independent of TRAF signaling. ^

Role of calcium in inflammation: Relevance to Alzheimer's disease

Alzheimer’s disease (AD) is neuropathologically characterized by excessive beta -amyloid (Aβ) plaques and neurofibrillary tangles composed of hyperphosphorylated tau in the brain. Although the etiology of genetic cases of AD has been attributed to mutations in presenilin and amyloid precursor protein (APP) genes, in most sporadic cases of AD, the etiology is still unknown and various predisposing factors could contribute to the pathology of AD. Predominant among these possible predisposing factors that have been implicated in AD are age, hypertension, traumatic brain injury, diabetes, chronic neuroinflammation, alteration in calcium levels and oxidative stress. Since both inflammation and altered calcium levels are implicated in the pathogenesis of AD, we wanted to study the effect of altered levels of calcium on inflammation and the subsequent effect of selective calcium channel blockers on the production of pro-inflammatory cytokines and chemokines. Our hypothesis is that Aβ, depending on it conformation, may contribute to altered levels of intracellular calcium in neurons and glial cells. We wanted to determine which conformation of Aβ was most pathogenic in terms of increasing inflammation and calcium influx and further elucidate the possibility of a link between altered calcium levels and inflammation. In addition, we wanted to test whether calcium channel blockers could inhibit the inflammation mediated by the most pathogenic form of Aβ, by antagonizing the calcium influx triggered by Aβ. Our results in human glial and neuronal cells demonstrate that the high molecular weight oligomers are the most potent at stimulating the release of pro-inflammatory cytokines IL-6 and IL-8 as well as increasing intracellular levels of calcium compared to other conformations of Aβ. Further, L-type calcium channel blockers and calmodulin kinase inhibitors are able to significantly reduce the levels of IL-6 and IL-8. These results suggest that Aβ-induced alteration of intracellular calcium levels contributes to its pro-inflammatory effect.

The Relevance of Marxist Academics

This commentary examines the relationship between a Marxist scholar and the institutional and societal environment of the university. The focus is on how a Marxist academic navigates the social, economic and political aspects of the university while attempting to maintain a commitment to class analysis and Marxism as political practice.

Relevance of the community college curriculum to the international student

The purpose of this study was to ascertain the perception of the level of satisfaction that international students have regarding the services and the relevance of the curriculum offered at Miami-Dade Community College. Trends and issues at universities and community colleges in providing services and an international curriculum for foreign students are outlined. Focus is on characteristics, personal and career needs as well as needs of national development for the students' countries. A sample of students from four developing nations was selected to qualitatively and quantitatively determine their level of satisfaction. The nations are the Bahamas, Colombia, Haiti and Pakistan. Students responses were recorded through group interviews, four personal interviews, an open ended questionnaire and a Likert scaled survey questionnaire. Matrix charts, mean calculations and one way analysis of variance were used to analyze data collected. Country of origin and major program of study were the variables used for statistical analysis. Information gathered through qualitative research presented a variety of perspectives and responses, both positive and negative. Students supplied specific examples of experiences and insights to help explain their various perceptions. Statistically, there were no significant differences between the variables of country of origin and major program of study regarding program services and relevance of the curriculum. Implications and recommendations for community college programs were outlined.

Transformative Learning Theory and Its Relevance to Managing Group Dynamics in a Competitive Work Environment

In any environment, group dynamics would exist. How we deal with it in a competitive work environment defines who we are using transformative learning. This paper provides useful information from a number of theorists who share perspectives on the complex nature of groups.