Establishing reactive astrocyte memory as a risk factor for aging-related neurodegenerative disease - Project Summary: Aging is the primary diver of neurodegenerative disease (ND), yet the etiology often remains elusive. Intriguingly, transient neuroinflammation (e.g. from acute infection) is a risk factor for developing ND decades later. This phenomenon has remained largely unexplored at the cellular and molecular level. My K99/R00 study focuses on the role of astrocytes in this process, a cell type that is often perceived as an inert neural support cell, however, they are essential for nervous system development, function, and regeneration, and have many parallels with innate immune cells. Research including my own reveals that astrocytes respond to neuroinflammation and injury with context-dependent molecular and functional changes referred to as “astrocyte reactivity”. In addition, we observed that astrocyte reactivity is mediated through substantial epigenetic changes, however, if these alterations are persistent after insult resolution is unclear. Indeed, if, or how, astrocyte reactivity resolves; and how transient astrocyte reactivity affects future insults remains unexplored. I propose a novel concept that: transient neuroinflammation results in long-lasting reactive astrocyte memory (RAM) – characterized by durable epigenetic changes, which allow for rapid gene alteration upon a subsequent insult. During aging, RAM can be inappropriately activated and contribute to ND onset and pathology. In this way, the astrocyte's response would mimic trained immunity described in the peripheral myeloid lineage where transient insults impart long-lasting “inflammatory memories” encoded by epigenetic changes. This inflammatory memory lowers the threshold for subsequent insults and enhances the cellular response. However, during aging, trained immunity can be inappropriately activated and contribute to pathologies such as cardiovascular disease and cancer. The objective of the current study is to establish the novel concept of RAM; determine the functional consequences of RAM in Alzheimer's disease (AD); and dissect the molecular mechanisms underpinning RAM. In Aim1 I will use mouse models of acute neuroinflammation and matched transcriptomic and epigenomic sequencing to define RAM with molecular precision. In Aim 2 I will use a mouse model of AD to functionally test the contribution of RAM to AD onset and progression. Finally, in Aim 3, I will determine the molecular mechanisms required for RAM formation, maintenance and recall by using astrocyte-specific gene knockdown methodology. This research will pioneer the concept and understanding of RAM and its role in ND. Data from this study can direct new therapeutics aimed at attenuating the maladaptive effects of neuroinflammation to limit ND pathology. This a critical goal for the future of medicine given the aging population and increasing global prominence of ND.
