A unique exosome-based approach to identify novel biomarkers for Alzheimer's disease - Project Summary/Abstract Alzheimer's disease (AD) has a huge disease burden, and AD cases are expected to increase by ~3-fold by the year 2050. There are several challenges in the early diagnosis of Alzheimer's disease, indicating a significant clinical need to develop additional non-invasive diagnostic tests, ideally from peripheral blood. Considering that sporadic Alzheimer's disease has a preclinical phase of up to decades before clinical symptoms arise, biomarker/s that would indicate the start of Alzheimer's disease would be of invaluable help for both prevention studies and therapeutic approaches. 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). These studies are promising, but these are limited by the fact that surface markers used for their isolation from plasma are generic and do not provide any information on the brain region from which they originate, and are not even CNS specific. Based upon our current knowledge, it is not possible to pullout exosomes from blood pertaining to Alzheimer's disease-relevant brain regions (e.g., hippocampus and entorhinal cortex); therefore, specific changes associated with Alzheimer's disease pathogenesis are currently missed. Our group has developed unique tools and techniques in the exosome field, which could be useful in solving this problem. These innovative tools could be useful in identifying unique proteins present only the surface of exosomes secreted by the hippocampus (ExoHippo) and entorhinal cortex (ExoEC) but absent in exosomes secreted by the cerebellum (ExoCB) at both mild-cognitive impairment (MCI) and Alzheimer's disease stages. The unique surface proteins will be used to pullout ExoHippo and ExoEC from blood and analyze for biomarkers of Alzheimer's disease. Following are the two integrated aims: I. To identify unique proteins present on the surface of exosomes secreted by hippocampus and entorhinal cortex in Alzheimer's disease. II. To isolate and characterize hippocampus- and entorhinal cortex- specific exosomes from plasma. Proposed studies are highly innovative, as currently, we lack any information about brain region-specific exosomes. Successful outcomes will have a significant impact in developing novel, early and reliable biomarkers for Alzheimer's disease. Further, this approach offers a less invasive way to discern the molecular pathogenesis of Alzheimer's disease.
