Molecular Changes that Predispose Worse Stroke Outcomes in Reproductively Senescent Females and Potential Therapeutic Targets

Abstract

Stroke is a leading cause of death and long-term disability in the United States. Women over the age of 55 have a higher lifetime risk of stroke and worse outcomes after stroke compared to men of the same age[1]. However, women do not have an increased risk of stroke across their lifetime. In premenopausal (45-55) age groups, women have a lower risk for and better outcomes after stroke as compared to age-matched men. Around the perimenopause phase, women’s stroke risk meets and then in later ages exceeds that of men[2]. This is largely thought to be due to the loss of neuroprotective ovarian hormones that accompanies menopause, though the Women’s Health Initiative demonstrated that hormone replacement therapy is not a viable option for mitigating stroke risk, as women in the group who received hormone replacement therapy experienced more strokes and more stroke-related mortality than women in the placebo group[3]. This thesis will therefore examine molecular changes beyond ovarian hormone synthesis that coincide with the onset of reproductive senescence and potential therapeutic interventions that could be investigated to develop stroke therapies for the older female demographic. Chapter 1 implicates the aging ovary as a depot of immune cells that responds to stroke by extravasating inflammatory immune cells, and that removing this extra pool of immune cells improves acute stroke outcomes. Chapter 2 characterizes epigenetic changes in the aging astrocyte, identifying miR-20a-3p as a neuroprotective microRNA (miRNA) by altering mitochondrial function in astrocytes, which may spare neuronal loss. Finally, Chapter 3 describes dysfunction in the aging mitochondria that can be modulated by miR-20a-3p treatment to astrocytes. These chapters together identify three distinct therapeutic targets that show age-related changes in the reproductively senescent female that could be used to develop novel stroke therapeutics for this demographic.