Neuroinflammation in an Alzheimer's Disease Animal Model and the Effectiveness of Selective Suppression of Glial Activation

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There is increasing evidence that links chronic activation of glial cells and the subsequent self-propagating cycle of neuroinflammation to the neurodegenerative progression of Alzheimer's disease (AD). Nevertheless, attempts to identify currently approved drugs capable of safely attenuating the neuroinflammatory processes in AD have proven disappointing to date, and the development of novel therapies has been hampered by the lack of an animal model with robust neuroinflammation that is capable of recapitulating disease pathology in a reasonable amount of time. Our goal was to test the hypothesis that neuroinflammation plays a role in the development of AD-relevant endpoints in animal models and that this neuroinflammation constitutes a feasible drug discovery target for the development of AD therapeutics. Towards this end, we first developed an AD-relevant mouse model that involves chronic infusion of beta-amyloid 1-42 (A1-42). This model recapitulates many of the hallmarks of AD, including neuroinflammation and neurodegeneration, in a timeframe more amenable to the recursive nature of drug discovery research than the currently available transgenic models. Utilizing the A infusion model, we also document the importance neuroinflammation plays in pathogenesis by showing increased neurodegeneration in genetically-modified mice predisposed to neuroinflammation. In addition, we show that treatment with a novel aminopyridazine anti-neuroinflammatory compound is able to ameliorate the inflammatory, neurodegenerative, and behavioral deficits induced by A infusion. Finally, we show that effective anti-neuroinflammatory therapy need not suppress the systemic immune system, a serious concern in chronic treatment of an elderly population. Overall, the results contribute to the increasing body of evidence that supports a critical role for neuroinflammation in AD progression. Our studies also provide a new mouse model that has robust, reproducible, and rapid development of AD-relevant endpoints through which to conduct drug discovery research. Finally, our data demonstrate as a proof-of-principle that anti-neuroinflammatory therapy can attenuate disease-relevant endpoints in an AD animal model without suppression of vital systemic inflammatory and immune responses.

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  • 05/10/2018
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