Thursday, November 21, 2024
11/21/2024
ABSTRACT Diabetes mellitus (DM) impairs cerebral waste clearance (CWC) and induces cerebral vascular dysfunction, resulting in cognitive decline. The relationships between CWC and diabetic status have not been fully investigated. Cerebral endothelial cells constitutively release exosomes, which mediate intercellular communication. We have demonstrated that administration of exosomes isolated from cerebral endothelial cells (CE-Exo) of healthy adult rats to DM rats improves cognitive function, minimizes DM-induced cerebral vascular dysfunction and increases CWC. Waste clearance from the brain parenchyma has an important role in regulating neurological diseases7, 15-22. We have found increased impairment of the CWC with severity of DM which highly correlated to cognitive deficits in DM rats (Fig 2&3)12. Currently, studies of efflux pathways of the soluble β- amyloid (Aβ) within the brain parenchyma have conflicting results between intramural periarterial drainage along the opposite direction of arterial flow and glymphatic perivenous efflux7, 23, 24. The glymphatic, vascular and meningeal lymphatic (ML) pathways are all involved in CWC3, 7, 20-22. We have demonstrated that highly sensitive MRI methods using the superparamagnetic iron oxide (SPIO) enhanced susceptibility weighted imaging (SPIO- SWI) permit detection of cerebral microvessels and evaluation of CWC in glymphatic, vascular and ML pathways (Fig 4-6)3, 25, 26. We also performed clinical translation of MRI measurements for CWC and found that the reduced clearance rate from both the glymphatic and ML pathways was significantly associated with aging in patients14. However, several critical issues related to clinical translation of CWC have not been resolved. Based on our novel preliminary data, we posit that the SPIO-SWI technique permits analysis of the relative contributions of the component vascular, glymphatic and ML systems to CWC, and thereby provides insight into their roles in mediating cognitive dysfunction in the aged diabetic animal with and without therapeutic intervention. The validation of MRI CWC measurements in current proposal could resolve the issues for clinical translation. To test these hypotheses, we will first (Aim 1) investigate the effects of CE-Exo treatment on alterations of DM associated CWC, vascular, molecular, and cognitive responses using MRI, fluorescent imaging, and immune- histopathological analysis, and then (Aim 2) investigate the effects of CE-Exo treatment on the component contributions of efflux pathways amount vascular, glymphatic and ML systems during waste clearance and their relationships with vascular dysfunction and cognitive deficits in the aged DM animals with and without therapeutic intervention.
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