The retina as a window to the brain in Alzheimer's disease? Insights from an animal model

Abstract

AbstractPurpose: The retina and the brain share the same embryonic origin, and the retina is considered an extension of the brain. In recent years, the concept ‘the retina as a window to the brain’ gained increasing interest to the study of brain degenerative diseases, such as Alzheimer's disease (AD). A better understanding of the natural history of AD and its temporal trajectories, also including alterations in the retina, requires longitudinal studies. Our main aim was to understand when changes (molecular, cellular, structural, physiological) start appearing in the retina and brain, how detected changes progress along time and if they can be correlated. We performed a longitudinal study in a triple transgenic mouse model of AD (3 × Tg‐AD), at 4, 8, 12 and 16 months of age.Methods: Behavioural assessment included the open field and novel object recognition (assessment of recognition memory) tests. The levels of amyloid β (Aβ) and hyperphosphorylated tau, two hallmarks of AD, were assessed in the hippocampus, a brain region associated with memory (impairment). By magnetic resonance imaging (MRI) we assessed hippocampal and visual cortex structural integrity (voxel‐based morphometry). Retinal structure and physiology were evaluated in vivo using optical coherence tomography (OCT) and electroretinography (ERG).Results: 3 × Tg‐AD animals presented altered locomotor activity, and recognition memory impairment at all time points. Significant reduction of hippocampal and visual cortex volumes started early, at month 4, and was maintained until 16 months. The overall retinal thickness of 3 × Tg‐AD mice, as well as the thickness of several retinal layers, decreased at all time points, except for the outer nuclear layer, where an increased thickness was observed. Regarding retinal physiology, the amplitude of scotopic and photopic responses of 3 × Tg‐AD increased at all time points. Similarly, higher amplitude and lower phase values were observed in the photopic flicker response. No differences were found in the activity of retinal ganglion cells. Moreover, a positive correlation between retinal thickness and visual cortex volume was found.Conclusions: This animal model (3xTg‐AD) mimics pathological and neurobehavioral features of AD, presenting early onset recognition memory impairment and hippocampal reduced grey matter volume. Moreover, 3xTg‐AD mice show similar neural changes in the retina and brain visual cortex, namely retinal and brain thinning. These observations support the possibility of using the retina as an additional tool for the early diagnosis and therapeutic monitoring of AD.Support: Santa Casa Mantero Belard Award 2015 (MB‐1049‐2015), FCT (SFRH/BD/52045/2012, SFRH/BPD/93672/2013, PEst UID/NEU/04539/2013, UID/NEU/04539/2019, UIDB/04539/2020 and UIDP/04539/2020, and MEDPERSYST SAICTPAC/0010/2015), COMPETE‐FEDER (POCI‐01‐0145‐FEDER‐007440 and POCI‐01‐0145‐FEDER‐016428) and Centro 2020 Regional Operational Programme (CENTRO‐01‐0145‐FEDER‐000008: BrainHealth 2020 and CENTRO‐01‐0145‐FEDER‐000016:BIGDATIMAGE).