Abstract WP238: Glymphatic System Dysfunctions Contributes To The Progression Of Cognitive Decline In A Rat Model Of Alzheimer's Disease

Abstract

Introduction: The aquaporin-4 (AQP4)-dependent glymphatic system mediates β-amyloid (Aβ) clearance. Using TgF344-AD rats that recapitulate clinical hallmarks of Alzheimer’s disease (AD), we examined longitudinal alterations of the AQP4-glymphatic system during the progression of Aβ deposition and cognitive decline. Methods: Male and female TgF344-AD rats (n=34, 18 male and 16 female) and wildtype (WT) littermates (n=30, 15 male and 15 female) rats at the ages of 6, 10, and 20 months (M) were subjected to an array of cognitive function tests. Aβ and AQP4 were measured using immunohistochemistry and the glymphatic system was measured using magnetic resonance imaging (MRI). Results: Compared to age-matched WT rats, TgF344-AD rats showed progressive cognitive deficits measured by odor recognition, social interaction, and Morris water maze tests starting from 10M and declining through 20M with worse cognitive deficit in female rats. Compared to WT rats, a significant reduction of para-arteriole AQP4 started at 6M (21±7%) and progressed to microvessels (55±12%) in the hippocampus and cortex through 20M, while Aβ deposition nearby reduced AQP4 started at 6M (6±2%) and widely expanded during 10M (31±9%) to 20M (42±7%). Aβ deposition was significantly correlated to cognitive deficit with R 2 of 0.95. During 10M to 20M extravascular albumin deposition was detected. MRI analysis revealed that TgF344-AD rats exhibited significantly decreased glymphatic clearance rate of Gd-DTPA starting at 10M, which was further aggravated at 20M. Conclusion: Our data demonstrate that female TgF344-AD rats have worse cognitive deficits and increased loss of AQP4 prior to cognitive deficits, Aβ deposition, and dysfunction of the glymphatic system. These data support that the AQP4-dependent glymphatic system plays an important role in mediating the progression of AD pathologies in the rat.