Project 3

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SUMMARY/ABSTRACT PROJECT R-3 The Role of Inflammation in Ad-Related Network Dysfunction in Mice (Dr. Hyman) Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by a progressive loss of memory function. Much research has concentrated on the pathological hallmarks of AD, amyloid-beta (Aβ) plaque deposition, tau hyperphosphorylation, neurofibrillary tangle formation, and the progressive loss neurons and synapses. Recently, studies have shown that immune activation, in the form of neuroinflammation and associated microglial activation, may contribute to progression of the classic AD pathologies, but the role neural inflammation plays in memory impairments observed in AD patients is unknown. Memory formation and retrieval are the products of interconnected networks of brain structures including the hippocampus (HC) and anterior cingulate cortex (ACC). Work with transgenic animal models that develop AD pathologies (Aβ deposition or tau hyperphosphorylation) has revealed altered electrical activity in the HC prior to the development of mass amyloidosis or tauopathy. This type of altered network activity may explain the appearance of memory deficits early in AD progression. All of the different transgenic models show severe neuroinflammation, however, whether the network dysfunction is due to the immune response or the classic AD pathologies remains unknown. Investigating the impact of neuroinflammation on memory-linked network activity can help to identify future therapeutic targets and potential biomarkers. Project 3 will investigate the effects of chronic or acute neuroinflammation on HC and ACC network activity. We will examine whether neuroinflammation affects different stages of memory processing (encoding, consolidation, retrieval) and whether the effects are localized to the HC or ACC or if they alter interactions between these areas. We plan to correlate our electrophysiological findings with markers of neuroinflammation to better understand how these factors work together in altering network activity. Next, we will examine whether increased neuroinflammation exacerbates the altered network activity observed in early stage pathology Aβ and tau transgenic models. If neuroinflammation leads to increased network dysfunction in the HC and ACC, these results support our overall hypothesis that NI itself is impairing memory network activity. These data will provide valuable information for a mechanism through which memory impairments appear in AD and AD transgenic animal models.