Wednesday, January 15, 2025
1/15/2025
Abstract Alzheimer’s disease (AD) remains one of the most unmet medical challenges in our society. In the AD, neuroinflammation has been increasingly recognized to play a central role in the pathogenesis of AD, in addition to extracellular amyloid plaques and hyperphosphorylated tau based neurofibrillary tangles. Although the role of innate immunity especially represented by microglia is well-established in AD, it is far less understood and established about whether and how the T or B cell-mediated adaptive immunity is involved in AD pathogenesis. In particular, whether there are brain- and AD-specific antigens to activate adaptive immunity and how these antigens travel to peripheral remain to be investigated. Exosomes (size 40-100 nm), a major type of secreted extracellular vesicles (EVs), are derived from intraluminal vesicles (ILV) that are budded inwardly from the early endosomal compartment and are released from multiple vesicular bodies (MVB) during the maturation of endosomes. EVs and exosomes secreted from various CNS cell types have emerged as a novel and important intercellular pathway in the. Exosome-mediated secretion has also been implicated in initiation and propagation in AD. Although exosomes secreted from various peripheral cell types especially immune and tumor cells trigger immune responses, whether and how CNS-derived exosomes are immunogenic remains unexplored. By employing cell-type specific ILV/exosome reporter (hCD63-GFPf/f) mice we recently generated, we showed that astroglia-derived exosomes are associated with Aquaporin 4+ (Aqp4+) perivascular end feet/blood vessel in the brain. hCD63-GFP+ astroglial exosomes can also be detected in blood serum of LPS-injected (but not control) Glast-CreER+CD63-GFPf/+ mice. Excitingly, exosomes secreted from “reactive” astroglia (RAEs) strongly activate CD4+ and CD8+ T cells in vitro and in vivo. Based on previous studies and our preliminary results, we propose to investigate the following aims: 1) Determine pathological efflux of CNS cell-type specific exosomes from brain and their entry into peripheral circulation in AD models; 2) Determine antigenicity of AD- relevant astroglial exosomes in activating T cells in vitro and in vivo. We have generated a large amount of preliminary data to support our rationales and to demonstrate feasibility for proposed aims. We will employ mouse genetics, virus injections, immunohistochemical (IHC) analysis and in vivo two-photon imaging, primary cultures, FACS, and biochemical approaches to investigate these two aims. Results from this project will determine the efflux changes of neuron or astroglial exosomes from the brain and these exosomes’ entry into peripheral circulation in AD models. In addition, our current study will investigate how T cells respond to “reactive” astroglial exosomes. As reactive astroglia is commonly observed in neurodegenerative diseases including AD, this will potentially unveil new mechanisms how T cells are involved in AD pathogenesis and help define specific brain signals to activate T cells in AD, which subsequently facilitate the therapeutic development.
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