Retinal Vascular Physiology Biomarkers in a 5XFAD Mouse Model of Alzheimer’s Disease

Abstract

Purpose : Alzheimer’s disease (AD) is a neurodegenerative disorder that lacks biomarkers for early diagnosis. The retina displays many characteristics of the AD brain, such as accumulation of amyloid beta (Aβ) oligomers and loss of function. In AD patients, changes in retinal venous velocity (V) and vascular oxygen saturation have been reported. These parameters as well as retinal oxygen metabolism (MO₂) and delivery (DO₂) have not been investigated in animal models of AD. The purpose of the study was to test the hypothesis that alterations in retinal arterial and venous diameter (D_A, D_V), V, and total retinal blood flow (TRBF), coupled with MO₂ and DO₂ are present in the five-familial AD (5xFAD) mice.

Methods : A total of 16 5xFAD and 16 wildtype (WT) mice were evaluated (age: 3 months). D_A and D_V were measured from retinal images, and V was determined by fluorescence microsphere imaging to calculate TRBF. Phosphorescence lifetime images were analyzed to derive arterial and venous oxygen contents (O_2A, O_2V) and arteriovenous oxygen content difference (O_2AV). MO₂ and DO₂ were calculated from TRBF, O_2A and O_2AV. Data were available in 13 of 16 mice in each group. Retina and brain tissues were evaluated by ELISA assays to determine Aβ42 levels in WT (N=4) and 5xFAD mice (N=6).

Results : In the WT group, D_A, D_V, V, and TRBF were 27±2 μm, 30±3 μm, 11.1±3.2 mm/s, and 1.73±0.52 μl/min, respectively. In the 5xFAD group, Dv (33±3 μm) was increased, while V (7.1±1.4 mm/s) was reduced (P≤0.04). No significant differences were detected in D_A and TRBF (P≥0.3). O_2A, O_2V, and O_2AV were 6.5±1.4 mLO₂/dL, 2.8±1.9 mLO₂/dL, and 3.7±1.3 mLO₂/dL in the WT group, respectively. In the 5xFAD group, O_2A (7.8±1.2 mLO₂/dL) and O_2V (4.3±1.6mLO₂/dL) were increased (P≤0.04), while no significant differences were detected in O_2AV (P=0.8). In the WT group, MO₂ and DO₂ were 57±16 nLO₂/min and 107±39 nLO₂/min, respectively. No differences were detected in MO₂ and DO₂ in the 5xFAD group (P≥0.1). Retinal Aβ42 was 2.4±0.8 pg/mg in the WT group and was increased in the 5xFAD group (5.9±2.9 pg/mg; P=0.04). In the WT group, brain Aβ42 was 1.5±0.5 pg/mg and was increased in the 5xFAD group (5.4±1.3 pg/mg; P=0.0005).

Conclusions : Taken together, retinal D_V, O_2A, and O_2V were increased, while V was decreased, whereas MO₂ and DO₂ were not altered in 5xFAD mice with elevated levels of Aβ42 protein in the retina and brain.

This is a 2021 ARVO Annual Meeting abstract.