Parallels between retinal and brain pathology and response to immunotherapy in old, late-stage Alzheimer's disease mouse models.

ABSTRACT

Despite growing evidence for the characteristic signs of Alzheimer's disease (AD) in the neurosensory retina, our understanding of retina-brain relationships, especially at advanced disease stages and in response to therapy, is lacking. In transgenic models of AD (APPSWE/PS1∆E9; ADtg mice), glatiramer acetate (GA) immunomodulation alleviates disease progression in pre- and early-symptomatic disease stages. Here, we explored the link between retinal and cerebral AD-related biomarkers, including response to GA immunization, in cohorts of old, late-stage ADtg mice. This aged model is considered more clinically relevant to the age-dependent disease. Levels of synaptotoxic amyloid ß-protein (Aß)1-42, angiopathic Aß1-40, non-amyloidogenic Aß1-38, and Aß42/Aß40 ratios tightly correlated between paired retinas derived from oculus sinister (OS) and oculus dexter (OD) eyes, and between left and right posterior brain hemispheres. We identified lateralization of Aß burden, with one-side dominance within paired retinal and brain tissues. Importantly, OS and OD retinal Aß levels correlated with their cerebral counterparts, with stronger contralateral correlations and following GA immunization. Moreover, immunomodulation in old ADtg mice brought about reductions in cerebral vascular and parenchymal Aß deposits, especially of large, dense-core plaques, and alleviation of microgliosis and astrocytosis. Immunization further enhanced cerebral recruitment of peripheral myeloid cells and synaptic preservation. Mass spectrometry analysis identified new parallels in retino-cerebral AD-related pathology and response to GA immunization, including restoration of homeostatic glutamine synthetase expression. Overall, our results illustrate the viability of immunomodulation-guided CNS repair in old AD model mice, while shedding light onto similar retino-cerebral responses to intervention, providing incentives to explore retinal AD biomarkers.