Characterizing The Protection Of An N-Terminal Active Core Peptide Within Β-Amyloid Against Β-Amyloid Neurotoxicity
Characterizing The Protection Of An N-Terminal Active Core Peptide Within Β-Amyloid Against Β-Amyloid Neurotoxicity
| dc.contributor.author | Forest, Kelly | |
| dc.contributor.department | Cell & Molecular Biology (Neuro) | |
| dc.date.accessioned | 2019-05-28T19:40:36Z | |
| dc.date.available | 2019-05-28T19:40:36Z | |
| dc.date.issued | 2018-05 | |
| dc.identifier.uri | http://hdl.handle.net/10125/62243 | |
| dc.title | Characterizing The Protection Of An N-Terminal Active Core Peptide Within Β-Amyloid Against Β-Amyloid Neurotoxicity | |
| dc.type | Thesis | |
| dcterms.abstract | Alzheimer’s disease (AD) is the most common cause of dementia in the aging population. As the disease progresses, AD leads to cognitive deficits affecting memory, changes in personality, and language dysfunction. AD is characterized by the pathological extracellular accumulation of fibril β-amyloid (Aβ) into senile plaques and the intraneuronal accumulation of the microtubule-associated protein tau as neurofibrillary tangles. Initially, insoluble fibrillary Aβ was believed to be central to disease pathogenesis, but more recent evidence implicates soluble oligomeric Aβ as the trigger behind the earliest cognitive deficits in AD. Under normal conditions, Aβ at low, physiological levels (pM) functions as a positive neuromodulator, enhancing synaptic plasticity and function. In addition, mouse models lacking Aβ show deficits in cognitive function and loss of synapses, suggesting, therefore, a vital role of Aβ in the maintenance of synaptic activity. On the other hand, pathological levels of Aβ (high nM-μM) cause irreversible degeneration of neuronal processes and the loss of synaptic function and connections in select areas of the brain. Previously, we reported that an endogenous N-terminal fragment derived from full-length Aβ retains the latter’s positive neuromodulatory activity and, notably, protects against Aβ-induced synaptic and memory deficits. Furthermore, through subsequent mutational analysis, we found a core sequence (YEVHHQ: N-Aβcore) within the N-terminal fragment accounting for its activity. Here, we aimed to characterize the neuroprotective potential of the N-Aβcore against Aβ-induced neuronal and synaptic damage, while elucidating the neuroprotective mechanism(s) of the N-Aβcore. Utilizing a neuronal toxicity model (rodent hybrid neuroblastoma cells transfected with α4β2 nicotinic acetylcholine receptors, nAChRs), the N-Aβcore was shown to retain receptor-linked activity. Subsequent mutational analysis demonstrated that the two histidine residues, and to a lesser degree, the tyrosine residue in the N-Aβcore are essential for this activity. In comparison to the sustained-elevated Ca2+ response elicited by Aβ, the N-Aβcore and N-terminal fragment displayed differential Ca2+ responses, suggesting the activation of an alternative, Aβ-independent pathway. In addition, the N-Aβcore was shown to be neuroprotective against Aβ-induced oxidative stress, ER stress, mitochondrial dysregulation, apoptosis, and synaptic dysfunction. We have also previously reported an increase in activity of various mitogen-activated protein kinases (MAPKs) in response to prolonged, sustained Aβ exposure. We therefore addressed whether the N-Aβcore has an impact on Aβ-linked MAPK activation. In our neuronal toxicity model, the N-Aβcore reduced the Aβ-induced MAPK activity. Interestingly, preliminary evidence indicates that low levels (pM) of the N-Aβcore nearly abolished c-Jun N-terminal kinase (JNK) activity. Furthermore, low levels of the N-Aβcore showed an increase in cAMP response element-binding protein (CREB) activity and expression, which has been shown to be downregulated in AD and AD models. Taken together, these findings suggest that the N-Aβcore is neuroprotective against Aβ-induced neuronal and synaptic toxicity by partially inhibiting Aβ binding to target receptors and subsequently activating an Aβ-independent neuroprotective pathway. | |
| dcterms.description | Ph.D. Thesis. University of Hawaiʻi at Mānoa 2018. | |
| dcterms.language | eng | |
| dcterms.publisher | University of Hawaiʻi at Mānoa | |
| dcterms.rights | All UHM dissertations and theses are protected by copyright. They may be viewed from this source for any purpose, but reproduction or distribution in any format is prohibited without written permission from the copyright owner. | |
| dcterms.type | Text |
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