Award Date

8-2010

Degree Type

Dissertation

Degree Name

Doctor of Philosophy in Biological Sciences

Department

Life Sciences

First Committee Member

Andrew J. Andres, Chair

Second Committee Member

Steven deBelle

Third Committee Member

Frank van Breukelen

Fourth Committee Member

Allen Gibbs

Graduate Faculty Representative

Bryan Spangelo

Number of Pages

111

Abstract

Dominant mutations in Presenilin (Psn) have been correlated with the formation of Aß- containing plaques in patients with inherited forms of Alzheimer's disease (AD). However, a clear mechanism directly linking amyloid plaques to the pathology of familial or sporadic forms of AD has remained elusive. Thus, recent discoveries of several new substrates for Psn protease activity have sparked alternative hypotheses to explain the preclinical symptoms of AD. CBP (CREB-binding protein) is a haplo- insufficient transcriptional co-activator with histone acetyltransferase (HAT) activity that has been proposed to be a downstream target for Psn signaling. Individuals with reduced CBP levels have cognitive deficits that have been linked to several neurological disorders. However, there are contradictory reports in the vertebrate literature regarding the relationship between Psn activity and CBP levels. This dissertation using Drosophila melanogaster, provides evidence for the first time that Psn is required for normal CBP levels and for maintaining global acetylations of the central nervous system of the adult fly. This work also demonstrates that adult flies conditionally compromised for CBP display an altered geotaxis response to gravity that likely reflects a neurological defect.

The association between Psn and CBP is most likely not direct, but through a signaling molecule released via Psn-mediated substrate processing. One possible candidate for this intermediate molecule is the transmembrane receptor Notch. Notch is attractive because it has been shown previously to be required for long-term memory, and I have provided evidence here that suggests Notch is required for neurite outgrowth through the culturing of primary neurons of the mushroom body (a region known to be important for learning and memory in flies). In addition I have located putative DNA binding sites for the Notch transcription factor Su(H) in the CBP enhancer, which suggests a regulatory role for Notch in CBP transcription. Although this is an attractive model, my data do not support it. Therefore it is likely that Notch and Psn/CBP control functions of the adult CNS through independent signaling molecules or pathways. If the model proves correct for vertebrates, it will have a significant impact on the development of new therapies and pharmaceuticals agents for the treatment of Alzheimer's disease.

Keywords

Alzheimer's disease – Etiology; Drosophila melanogaster; Fruit flies; Genetic transcription; Presenilins

Disciplines

Molecular and Cellular Neuroscience | Neuroscience and Neurobiology

Language

English


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