Vascular Inflammation and Exosomes as Mediators in Aging and Dementia

University Of California At Davis, Davis CA

Investigators

Abstract

Aging is characterized by the development of systemic inflammatory changes, organ dysfunction and frailty. Aging is associated with increased oxidative stress and inflammation, which leads to impaired vascular repair, increased inflammation and increased monocyte adhesion. This is accompanied by the development of senescent (Sen) endothelial cells (EC), which originally were thought to be benign, but are now known to be a source of a sustained inflammatory output known as the senescence associated secretory phenotype (SASP) and other deleterious effects that contribute to the overall decline and frailty seen with aging. The vasculature has been under investigated as a contributor to the development of Alzheimer?s and other dementias, all of which are diseases predominantly associated with aging. We hypothesize that senescent (Sen) endothelial cells (ECs), which accumulate with aging, create a pro-inflammatory environment that adversely affects the blood brain barrier (BBB) and contributes to neuropathology implicated in age-associated dementias such as Alzheimer?s disease (AD). To this end we will use an established, well-characterized in vitro model of human Sen EC to study the effects of the SASP and exosomes derived from Sen EC, on human BBB integrity and neurons in culture. We will also analyze the content, including miRNA, of exosomes produced by Sen vs. early passage (EP) EC derived from the same donor, and determine whether co-culture with Sen ECs, SASP or exosomes increases the susceptibility of different neural cells to the toxicity of A?42 peptides. Lastly, we will investigate whether exogenous administration of exosomes derived from Sen EC compromises BBB integrity and promotes AD-relevant neuropathology in vivo in male and female TgF344-AD rats, which are an early onset Alzheimer's model. Age- and sex-matched congenic wild type rats will be used as controls. BBB integrity, neuroinflammation, neuronal connectivity, neurofibrillary tangles and amyloid plaques will be studied using state of the art imaging modalities as well as biochemical and cellular analysis. This work has the potential to identify new mechanisms contributing to the development of dementias, such as Alzheimer?s, which is approaching epidemic proportions in our aging population. Such findings have the potential to lead to new therapeutic targets.