Project R-3 – Dr. James Hyman

Dr. James Hyman

Dr. James Hyman

The role of neuroinflammation in AD-related network dysfunction in mice.

Alzheimer’s disease (AD) is a neurodegenerative disorder that is characterized by a progressive loss of memory function. Much research has concentrated on the pathological hallmarks of AD, amyloid-beta (Aβ) plaque deposition, tau hyperphosphoralation and neurofibrillary tangle formation, and the progressive loss neurons and synapses. Recently, literature has shown that immune activation, in the form of neuroinflammation and associated microglial activation, may contribute to the progression of the classic AD pathologies. It is not known what role neural inflammation itself plays in memory impairments observed in AD patients. 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 hyperphosphoralation) has revealed altered electrical activity in the HC occurring prior to the development of mass amyloidosis or tauopathy. This type of altered network activity potentially explains why memory problems appear early in AD progression. Since all these different transgenic models also have severe neuroinflammation, it is not known if the network dysfunction is due to the immune response or the classic AD pathologies. Better understanding the role of neuroinflammation in memory-linked network activity will help to identify future therapeutic targets and potential biomarkers.

            Project 3 will determine whether chronic or acute neuroinflammation differentially affect HC and ACC network activity. We will examine whether different stages of memory processing (encoding, consolidation, retrieval) are more or less vulnerable to neuroinflammation and whether these effects are localized to the HC or ACC or do they affect the interactions between these areas. We will also correlate our electrophysiological findings with markers of neuroinflammation to better understand how these factors work together. Next, we will examine whether increased neuroinflammation exacerbates altered network activity found in early stage pathology Aβ and tau transgenic models. If neuroinflammation leads to increased network dysfunction in the HC and ACC, it will 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.