Purpose The diagnosis of Alzheimer's disease (AD) is difficult. Since AD patients have visual problems, even before AD diagnosis, and retina is part of the CNS, we aim to understand whether retina could be used as a window to the brain, and for earlier and better diagnosis of AD. Methods To achieve this, we are performing a longitudinal study to evaluate potential changes in several molecular, cellular, structural and physiological parameters in the retina of a triple transgenic mouse model (3xTg‐AD), comparing to age‐matched wild‐type (C57BL6/129S) mice, at 4, 8 and 12 months (M) of age, by Western blot, immunohistochemistry, TUNEL assay, ERG, PERG and OCT. Results In 3xTg‐AD mice, at 8 and 12 M, the retinal thickness decreased significantly, and at 4, 8 and 12 M the scotopic b‐wave and photopic flicker amplitude increased. No differences were detected in PERG recordings. Amyloid beta protein was not detected in the retina of 3xTg‐AD at 4 and 8 M. The p‐Tau protein levels increased at 4 M, but not at 8 M. At 4 and 8 M, amyloid precursor protein, beta‐secretase 1, choline acetyltransferase, syntaxin and synaptophysin levels remained unchanged in the retina of 3xTg‐AD. Apoptotic cells (TUNEL+ cells) were not detected. Also, no alterations were detected in the immunostaining of vimentin in 3xTg‐AD, but GFAP immunostaining decreased at 8 M. Conclusions These results show that retinal thickness and function are early affected in a mouse model of AD. However, no molecular and cellular correlates were found in the majority of parameters evaluated in the retina, with the exception of p‐Tau and GFAP, at least in early timepoints. Support: Santa Casa Mantero Belard Award 2015 (MB‐1049‐2015); FCT Portugal, PEst (UID/NEU/04539/2013), COMPETE‐FEDER (POCI‐01‐0145‐FEDER‐007440); Centro 2020 Regional Operational Programme (CENTRO‐01‐0145‐FEDER‐000008: BrainHealth 2020).

Background: The concept 'the retina as a window to the brain' in Alzheimer´s disease (AD) has been explored in recent years since patients sometimes present visual alterations before the first symptoms of dementia. The retina is an extension of the brain and can be assessed by non-invasive methods. However, assessing the retina for AD diagnosis is still a matter of debate. Using the triple transgenic mouse model of AD (3xTg-AD), this study was undertaken to investigate whether the retina and brain undergo similar molecular and cellular changes during the early stages of AD pathology, and if the retina could anticipate the pathological alterations occurring in the brain. Methods: We used the 3xTg-AD and wild-type mice (C57BL6/129S), at 4 and 8 months of age, and assessed several parameters in the retina and brain (hippocampus and cortex): amyloid-beta (Aβ) and hyperphosphorylated tau (p-tau) levels, barrier permeability, cell death, neurotransmitter levels and glial changes. Results: We detected increased Aβ levels in the hippocampus and cortex and increased p-tau in the hippocampus, retina and cortex of 3xTg-AD mice. The brain and retinal barriers were unaffected. At 4 months, the content of some synaptic proteins increased in the brain but not in the retina. No cell death, including retinal ganglion cells loss, was detected in 3xTg-AD mice. Overall, no changes were observed in glutamate and GABA levels in all regions. There was an increase in astrogliosis in the hippocampus at 4 months and a decrease in the retina at 8 months. No changes were detected in Müller cells reactivity. Furthermore, we did not find changes in the number of microglia in 3xTg-AD mice, but we detected a different profile in microglia branching in the hippocampus and retina, at 4 months, where the number and length of the processes increased in the hippocampus and decreased in the retina. Conclusions: At the early stages of pathology, the retina, hippocampus and cortex of 3xTg-AD are not significantly affected, but already present some molecular and cellular alterations. The retina did not mirror the changes detected in the brain in this animal model of familial AD, and these observations should be taking into account when using the retina as a potential diagnostic tool for AD.