Kirkwood, Caitlin
(2015)
THE ROLE OF NEURONAL CALCIUM SENSOR PROTEIN VILIP-1 IN Aβ-INDUCED NEURONAL DEATH IN ALZHEIMER DISEASE.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
Alzheimer disease (AD) is the most prevalent form of dementia in the United States affecting an estimated 5.3 million individuals in 2015. Clinically, AD presents with progressive memory loss, decline in cognitive abilities, and behavioral changes. Neuropathologically, increased synaptic pathology and neuronal loss correlate with cognitive impairment in AD. While the specific neurobiological mechanisms underlying AD neuronal loss are not fully understood, a growing pool of evidence implicates soluble amyloid-β (Aβ) oligomers as a primary neurotoxic agent. Previous work has demonstrated that Aβ disrupts neuronal Ca2+ homeostasis, initiating a cascade of pathological events that ultimately culminate in widespread neuronal death. Recently, neuronal calcium sensor protein visinin-like protein 1 (Vilip-1) has been identified an AD-specific peripheral biomarker, however little is known about Vilip-1 in the AD brain. Previous work has alluded to associations between Vilip-1, Aβ, and neuronal death. VSNL1, the gene that encodes Vilip-1, coexpresses with genes related to AD throughout normal aging, notably amyloid precursor protein (APP), which is cleaved in the pathogenesis of AD to form Aβ. Vilip-1 immunoreactivity also associates with neuritic plaques in the neocortex of the human AD brain. Finally, overexpression of Vilip-1 in a cell line increased death rates following a Ca2+ challenge, suggesting Vilip-1 may play a functional role in neuronal loss. To determine if Vilip-1 plays a causal role in AD, first we investigated Vilip-1 levels in two regions of the human AD brain. Then we used model systems to evaluate the impact of Aβ on Vilip-1 expression and determined whether manipulation of Vilip-1 expression affected Aβ-induced neuronal death. We demonstrated that Vilip-1 is reduced within brain regions characterized by prominent neuronal loss in both AD and frontotemporal lobar degeneration (FTLD). We reported that Vilip-1 expression is not driven by Aβ. Finally, we found that Aβ-initiated neuron death was unaffected by the extent of Vilip-1 expression. Together, these data suggest that Vilip-1 is a general marker for neuronal loss in brain tissue rather than participant in an AD-specific neuronal death process. In addition, Vilip-1 may have value as a novel marker for neuronal integrity and loss in human brain tissue.
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| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
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| ETD Committee: |
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| Date: |
13 July 2015 |
| Date Type: |
Publication |
| Defense Date: |
29 April 2015 |
| Approval Date: |
13 July 2015 |
| Submission Date: |
16 June 2015 |
| Access Restriction: |
No restriction; Release the ETD for access worldwide immediately. |
| Number of Pages: |
174 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Medicine > Neurobiology |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
Alzheimer's disease, Vilip-1, neuron death, Aβ |
| Date Deposited: |
13 Jul 2015 12:46 |
| Last Modified: |
19 Dec 2016 14:42 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/25418 |
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