Wednesday, May 18, 2022
5/18/2022
Project Summary/Abstract The discovery of brain-derived exosomes in the circulation has led to studies examining their role as potential mediators as well as `liquid biopsies' for Alzheimer's disease and related dementias (ADRD). Studies to date appear promising but have several major limitations: performed in a limited number of archived samples at a single time-point; ignore racial/ethnic, gender, and genetic disparities in ADRD; lack concurrent assessment of established vascular and AD-related neuroimaging biomarkers paired with cognitive adjudication; and lastly, these studies are mainly focused on neuron-derived exosomes to the exclusion of other cellular constituents of the neurovascular unit (NVU). Further, recent studies have suggested that vascular disorders are associated with multiple dementia-related pathologies; however, no study has been able to systematically characterize plasma exosomes of NVU for biomarkers of ADRD and hypoxia. We have developed novel tools to isolate and characterize exosomes derived from all key cell types of the brain NVU [neuron-derived exosomes (NDE), astrocyte-derived exosomes (ADE), endothelial-derived exosomes (EDE), pericyte-derived exosomes (PDE) and supporting cells microglial-derived exosomes (MDE) and oligodendrocyte-derived exosomes (ODE)]. We detected and quantified ADRD biomarkers (e.g., Aß1-40, Aß1-42, and neurofilament light (NfL)) loaded in NVU exosomes from Wake Forest AD Research Center participants and related their levels to ADRD neuroimaging and biofluid biomarkers. Next, we seek to extend this approach to understand exosomal heterogeneity across various ages, gender, and races/ethnic groups in ADRD. To this end, we will leverage the Multi-Ethnic Study of Atherosclerosis Multisite Study of AD (MESA-MIND; R01AG058969, PI: Hughes) with a longitudinal diverse cohort of older adults. MESA-MIND aims to elucidate the contribution of subclinical vascular disorders to the ethnic disparities in ADRD. We will obtain blood samples from 1,000 participants representing the three most common racial/ethnic groups in the US (White: 30%, African American: 40%; and Hispanics: 30%) recruited to participate in both PET and MRI at three sites. The resources of MESA-MIND provide a unique opportunity to advance our understanding of NVU derived exosomal biomarkers of the vascular and AD specific contributions to dementia. Specific aims are: I. Quantify and relate ADRD biomarker levels in NVU exosomes with cognition and neuroimaging biomarkers of ADRD. II. Relate hypoxia signature in NVU exosomes with biofluid and neuroimaging biomarkers of ADRD. In both the aims, we will examine the heterogeneity of NVU exosomal number and content across important subgroups in ADRD (cognitive status, race/ethnicity, age, gender, and APOE-e4), which we expect to modify the relationships with neuroimaging biomarkers of ADRD (Aß-PET and MRI) and cognitive decline. Overall, the present study would lead to the development of novel blood-based exosomal biomarker development for both hypoxia and AD pathology. NVU exosomal biomarkers will also provide insight into the molecular links in the vascular contributions to ADRD.
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