Alzheimer’s disease (AD) is a progressive neurodegenerative disorder, with asymptomatic and symptomatic phases. Hallmark lesions of AD include extracellular deposits of fibrillar amyloid-β (A β) and intracellular Neurofibrillary tangle formations (NFTs). However, recent evidence seems to support soluble oligomeric forms of amyloid proteins as bioactive species in AD. Amyloid-β oligomers (Aβo), such as Aβ*56, Aβ dimers and trimers have been demonstrated to be synaptotoxic species in AD. In particular, one of these oligomers, Aβ*56, was found to cause cognitive decline in the AD mouse model Tg2576, despite the absence of plaques and neuronal loss. In addition, cross-sectional studies suggest its possible involvement in the asymptomatic or preclinical phase of AD. However, it is currently unclear how this specific oligomer (Aβ*56) influences cellular and molecular processes to lead to cognitive deficits. My thesis focused on how Aβ*56 is able to disrupt cognition at the cellular and molecular level. First, we demonstrate that Aβ*56 forms a complex with NMDA receptors (NMDARs) resulting in an aberrant increase in intracellular calcium driven by synaptic NMDARs and the specific activation of the Ca2+/calmodulin dependent protein kinase CaMKIIα. Active CaMKIIα induces selective pathological changes in tau in vivo and in vitro, involving hyperphosphorylation and missorting. Importantly, other forms of endogenous Aβ oligomers do not appear to trigger these effects. Furthermore, other kinases such as GSK3, Cdk5 and fyn are not modulated by Aβ*56 in vitro. Interestingly, CaMKII phosphorylation is elevated in brain tissue of aged individuals, correlating with Aβ*56 abundance. These findings indicate that distinct Aβ oligomers activate specific neuronal signaling pathways in a highly selective manner in vitro. By extrapolation, these observations may have important consequences relative to our understanding of the different stages of AD.
University of Minnesota Ph.D. dissertation. January 2016. Major: Neuroscience. Advisor: Sylvain Lesne. 1 computer file (PDF); viii, 119 pages.
Cellular And Molecular Mechanism Of Action Of The Amyloid-Beta Oligomer Abeta Star 56.
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