Document Type

Dissertation

Degree

Doctor of Philosophy

Department

Biology

First Advisor's Name

Ophelia Weeks

First Advisor's Title

Committee Chair

Second Advisor's Name

Daniel Paris

Third Advisor's Name

Fiona Crawford

Fourth Advisor's Name

Leung Kim

Fifth Advisor's Name

Lidia Kos

Keywords

neurodegeneration, calmodulin kinase inhibitors

Date of Defense

10-18-2007

Abstract

Alzheimer’s disease (AD) is neuropathologically characterized by excessive beta -amyloid (Abeta)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 Abeta depending on it conformation, may contribute to altered levels of intracellular calcium in neurons and glial cells. We wanted to determine which conformation of Abeta 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 Abeta by antagonizing the calcium influx triggered by Abeta.

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 Abeta. 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 Abeta induced alteration of intracellular calcium levels contributes to its pro-inflammatory effect.

Share

COinS