Lycium barbarum extracts preserve retinal function by rescuing synaptic loss in 3xTg mouse model of Alzheimer's disease

Abstract

Alzheimer's disease (AD) is a chronic neurodegenerative disease. Ocular abnormalities in patients with AD have been reported, including retinal ganglion cells (RGCs) loss, axonal degeneration in the optic nerve, Amyloid β plaque pathology. The Lycium barbarum extracts (LBE) have been demonstrated to be neuroprotective in various animal models of neurodegeneration. In the current study, we aim to investigate the effect of oral feeding LBE on structural and functional changes of retina in the 3xTg AD mouse model. Methods: 6 months old 3xTg-AD and C57/6J mice were treated by gavage with low (200mg/kg) or high (2g/kg) doses of LB hydrophilic extract daily for 3 months, while water treatment was used as a placebo control. Retinal function was evaluated by electroretinogram (ERG) at one month, two months and three months of gavage with a scotopic flash intensity of 3.0 cd.s/m2 and photopic flash intensity of 22.76 cd.s/m2. Amplitude and latency of ERG signals were filtered and analyzed by Axon pCLAMP. Mice were sacrificed after 3 months of treatment, and the eyes were harvested. Morphological changes of the retina were analyzed in cross-sections. Immunohistochemical staining (IHC) was performed with various primary antibodies including anti-Brn3a, anti-synaptophysin, and anti-PSD95. Results: ERG results showed that the scotopic retinal response of 3xTg-AD mice started to decline during 4-6 month of age, followed by a rapid decrease during 6-8 month. In this study, one month high doses LBE gavage group showed a significant increase of b-wave in scotopic ERG. The same tendency of b-wave preservation was observed at two months high doses LBE feeding without statistical significance and vanished at three months (9 months of age). In 9 months old AD mice, there were no significant differences in inner nuclear layer thickness, outer nuclear layer thickness, and RGC numbers compared to age-matched C57 mice, and no changes were observed after LBE treatment. However, presynaptic density in Inner plexiform layer but not outer plexiform layer was significantly increased in the LBE high dose treated AD mice, suggesting the presynaptic structure of retina was preserved. Conclusions: Our results indicated that at early- and mid-stage of AD, presynaptic changes in IPL contributed the most to b-wave decline and LBE gavage could preserve the retinal functional deterioration in 3xTg AD mice by preventing the synapse loss in IPL. The protective effect topped at one month gavage in ERG test and still detectable till the end of three-month-treatment by IHC. This study suggested that LB has the potential to be used as a neuroprotectant in AD-related vision loss.