Neuromodulation by a N-Terminal Beta Amyloid Fragment

Date
2014-09-26
Authors
Minezaki, Anne
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Nichols, Robert
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Biology
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University of Hawaii at Manoa
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Abstract
Beta amyloid (Aβ), a polypeptide found in the brain consisting of 38-43 amino acids, is generated via proteolytic cleavage of amyloid precursor protein (APP). Although multiple isoforms of Aβ exist, the 1-42 amino acid isoform (Aβ1-42) has been found to be the primary neurotoxic species in Alzheimer’s disease, formed via cleavage of APP by β-secretase and γ-secretase. However, it has been shown that a non-amyloidogenic pathway exists wherein Aβ is cleaved by another protease, α-secretase, ultimately resulting in the generation of a 1-15 amino acid fragment, termed the N-terminal Aβ fragment (Aβ1-15). It has shown that inhibition of γ-secretase leads to upregulation of α-secretase activity, possibly leading to increased levels of the N-terminal Aβ fragment. More intriguingly, the Aβ1-15 fragment may function as a potent non-toxic, neuromodulator. Thus, I am investigating: (1) the pathways involved in the regulation of production of the N-terminal beta amyloid fragment with a particular focus on the alpha secretase pathway and its potential modulation by regulators of alpha secretase activity and (2) whether the upregulation of the N-terminal beta amyloid fragment in culture is neuroprotective and/or neuromodulatory. Using immunoblot analysis, we have shown production of APP in FLAG-tagged APP-transfected neuroblastoma cells. In addition, preliminary results suggest that treatment with the γ-secretase inhibitor DAPT leads to greater processing of APP and possible generation of Aβ1-15. We anticipate the Aβ1-15 activity to lead to neuromodulation of nerve cell function.
Description
Keywords
beta amyloid (Aβ), N-terminal Aβ fragment (Aβ1-15), secretase
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iv, 35 pages
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