Dissecting the role of hippocampal exosomes in Alzheimer's disease pathogenesis

Wake Forest University Health Sciences, Winston-Salem NC

Investigators

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Abstract

Summary Alzheimer’s disease is the most common form of dementia and afflicts 5.8 million individuals in the US alone. Discovered over 100 years ago, there is still little known about what causes Alzheimer’s disease and more importantly, no therapies exist to treat, prevent, or slow Alzheimer’s disease progression. Impaired degradation and clearance of aggregated, toxic proteins is characteristic of Alzheimer’s disease. The release of exosomes has been suggested as an alternative pathway for cellular clearance. However, exosomes can also carry amyloid-β, the toxic protein that aggregates to form amyloid plaques, suggesting exosome secretion could also enhance extracellular spread of pathology. Nevertheless, current Alzheimer’s research has mainly focused on brain-derived exosomes isolated from circulating blood as potential biomarkers for Alzheimer’s disease. However, it is unknown whether these blood exosomes mimic the pool of exosomes found in the interstitial fluid (ISF) of brain regions susceptible to Alzheimer’s disease. Determining the relationship between these two exosome pools has exciting implications for not only facilitating Alzheimer’s diagnosis but also for understanding Alzheimer’s pathogenesis. Previous studies have examined exosomes from the extracellular space of brain tissue, but little is known about exosomes found in vivo in the ISF. In this proposal, I will use a novel approach to collect exosomes from the hippocampal ISF of unanesthetized, freely moving mice using in vivo microdialysis. I will then compare the ISF pool of exosomes from APP/PS1 mice, a mouse model of cerebral amyloidosis, with the ISF from wildtype mice. Moreover, I will investigate how the ISF pool from the hippocampus differs from the population isolated from the blood. I will also characterize how age, sex, and amyloid plaque pathology change exosome concentration and composition. It is imperative to examine alterations in brain ISF exosomes in order to gain more insight into the role of exosomes in Alzheimer’s pathogenesis and as effective biomarkers of Alzheimer’s disease. This proposal will shed further light on brain- derived exosomes in blood and examine whether they are accurate pictures of what is going on in the in vivo brain during Alzheimer’s progression.