Alzheimer's Disease (AD) is a progressive neurodegenerative disease and the most common form of dementia. It is characterized by the accumulation of amyloid beta (Aβ) and the microtubule-associated protein tau into extracellular senile plaques and intraneuronal neurofibrillary tangles, respectively, in the brain over the course of many years. Additional histopathological hallmarks of AD include synaptic dysfunction and loss, the loss of neurons in select brain regions, brain atrophy and more recently, the induction and chronic presence of neuroinflammation. Symptoms of AD arise decades after Aβ begins to accumulate in the brain and include increasing memory loss, cognitive deficits, personality changes and language dysfunction. AD is the sixth leading cause of death in the United States and poses a tremendous financial burden on the health care system. To date, a cure remains elusive and current treatments are only minimally efficacious, making research into AD imperative. The focus of the majority of AD research has been on the mechanisms involved in neuronal dysfunction and death; however, more recently a paradigm shift has occurred in the field, expanding the research into the role of glial cells in AD as well. Astrocytes and microglia, two types of glial cells, can modulate their phenotypic state depending on the signals present in the brain parenchyma. At physiological concentrations Aβ has positive neuromodulatory functions; however, the accumulation of soluble, oligomeric Aβ peptide to pathological concentrations (high nM to μM) activates astrocytes and microglia from a normal 'resting' state in which they provide many diverse and beneficial neuromodulatory functions, to a reactive phenotype that exacerbates neuronal death. In the prodromal stage of AD, when soluble oligomeric Aβ begins to accumulate, astrocytes and microglia activate to a neuroprotective phenotype and begin to phagocytose the peptide to reduce the concentration in the brain and, thus, mitigate the toxic effects of full-length Aβ. However, as the disease progresses, these cells convert to a reactive phenotype and secrete proinflammatory cytokines, reactive oxygen and nitrogen species, and complement proteins that contribute to the persistent neuroinflammation that is characteristic of AD. Our laboratory previously showed that the endogenous N-terminal fragment of Aβ, compassing residues 1-15/16, termed the N-Aβ fragment, retains the neuromodulatory functions of full-length Aβ. Through further structure-function studies we refined the activity of the N-Aβ fragment to a critical hexapeptide core sequence encompassing residues 10-15 (YEVHHQ), termed the N-Aβcore. We also reported that these two N-terminal Aβ fragments (collectively termed N-Aβ fragments), protect against full-length Aβ-induced cellular neurotoxicity and synaptic dysfunction in neurons as well as behavioral dysfunction in whole animals. Here, we aimed to characterize the neuroprotective potential of the N-Aβ fragment and the N-Aβcore against full-length Aβ-induced gliotoxicity via the modulation of the activation state(s) of astrocytes and microglia within a proinflammatory environment. Utilizing primary cortical glia cultures, I show that the N-Aβ fragment and N-Aβcore elicited differential calcium responses compared to full-length Aβ. In addition, concurrent administration of either of these N-Aβ fragments with Aβ mitigated the robust calcium responses in primary astrocytes and microglia with the application of Aβ alone. Moreover, I demonstrated that the N-Aβ fragment or N-Aβcore are able to mitigate the activation of these cells in two model systems, primary cortical glial cultures and organotypic slice cultures as well as reduce the expression of the proinflammatory cytokine TNFα and complement protein C3, two known neurotoxic proteins that contribute to disease progression with continued expression. Furthermore, the N-Aβ fragment and N-Aβcore were shown to attenuate oxidative stress,
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