Abstract WP491: HUCBC Treatment Promotes White Matter Remodeling and Improves Glymphatic Function and Cognitive Outcome in Rats With Vascular Dementia

Abstract

Aim: Vascular Dementia (VaD) accounts for nearly 20% of all dementia. We have investigated the therapeutic effects of human umbilical cord blood cells (HUCBCs) treatment of VaD and tested mechanisms such as that white matter (WM) remodeling and glymphatic function that contribute to improving cognitive outcome. Methods: Male rats (6-8m old) were subjected to a multiple microinfarct model (MMI, 500-800 cholesterol crystals injected into the internal carotid artery) of VaD, and 3 days later treated with PBS or HUCBC (5х10 6 , i.v.) n=6/group. Cognitive tests were conducted and rats sacrificed at 28 days after MMI. To evaluate glymphatic function, fluorescent tracers (Texas Red dextran, MW: 3 kD and FITC-dextran, MW: 500 kD) were injected into the cisterna magna over 30min at 14 days after MMI. Rats (6/group/time point) were sacrificed at 30min, 3h, and 6h and tracer movement analyzed using laser scanning confocal microscopy. Results: HUCBC treatment significantly improves short term memory (Novel object recognition test discrimination index: MMI: 35.6±3.6%; MMI+HUCBC: 74.2±4.3%; p<0.0001), long term memory (odor test discrimination index: MMI: 49.9±5.8%; MMI+HUCBC: 69.2±4.8%; p<0.01) and spatial learning and memory (Morris water maze test: decreased latency and increased % of time in target quadrant, p<0.05) compared to control MMI rats. HUCBC treatment significantly increases axon and myelin density, increases oligodendrocyte and oligodendrocyte progenitor cells number, and increases Synaptophysin expression in the brain compared to control MMI rats. HUCBC treatment of MMI in rats significantly improves glymphatic function by reversing MMI induced delay in cerebrospinal fluid penetration into the brain parenchyma via paravascular pathways as well as delayed waste clearance from the brain. HUCBC treatment significantly decreases serum protein expression of BACE1, S100, MCP-1, and TGF-β which may contribute to HUCBC induced therapeutic effects. Conclusions: HUCBC treatment of an MMI rat model of VaD promotes WM remodeling, anti-inflammatory effects and improves glymphatic function which in concert may contribute to the improvement in cognition and memory. Thus, HUCBC treatment warrants further investigation as a potential therapy for VaD.