Inhibition of amyloid beta oligomer formation, binding, and downstream tau phosphorylation: three potential therapeutic approaches for Alzheimer’s disease

Johnson, Elizabeth Anne

doi:https://doi.org/10.21985/n2-2xpj-8e57

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Inhibition of amyloid beta oligomer formation, binding, and downstream tau phosphorylation: three potential therapeutic approaches for Alzheimer’s disease

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Amyloid beta oligomers (AβOs) are a key instigator of neurodegeneration in Alzheimer’s disease (AD). The work presented in this thesis includes three disease-modifying approaches to disrupt pathological AβO-related mechanisms in AD: (1) inhibiting AβO buildup, (2) blocking AβO-induced tau phosphorylation, and (3) neutralizing AβOs. These three approaches were tested in primary hippocampal neuron cultures to which Aβ monomer or AβOs were applied. First, the small molecule NU-9, which was previously developed to provide protection in models of amyotrophic lateral sclerosis proteopathy, was shown in this work to additionally prevent buildup of neuron-binding AβOs. The mechanism of NU-9, which acted on a cellular target, was determined to be lysosome- and cathepsin B-dependent. Further, the buildup of neuron-binding AβOs in this model occurred by a dynamin- and cathepsin L-dependent intracellular trafficking mechanism. These results provide new insight into the mechanisms of pathological AβO buildup in neurons and uncover a novel avenue for protection against AβO accumulation with potential application to multiple neurodegenerative proteopathies. Second, the effect of specific inhibition of the neuronal isoform of nitric oxide synthase (nNOS) was tested. The results obtained in this work demonstrate the role of nNOS activation in AβO-induced tau phosphorylation, AβO formation, and modulation of spine morphology. These results support the conclusion that multiple forms of AD neurodegeneration may be nNOS-dependent and can be disrupted by specific inhibition of nNOS. Third, monospecific mono, di, and trivalent Nusc1 megamolecules were used to bind and neutralize AβOs, preventing AβOs from binding to neurons. Differential AβO binding and neutralization corresponded to megamolecule valency. These findings support the use of Nusc1-based megamolecules to robustly neutralize AβOs in AD. In this work, three promising avenues of potential therapeutic relevance to AD were investigated, and the results provided insight into the mechanisms of AβO buildup and AβO-instigated pathology.

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