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

Jonah Doustar, Altan Rentsendorj, Tania Torbati, Giovanna C. Regis, Dieu-Trang Fuchs, Julia Sheyn, Nazanin Mirzaei, Stuart L. Graham, Prediman K. Shah, Mitra Mastali, Jennifer E. Van Eyk, Keith L. Black, Vivek K. Gupta, Mehdi Mirzaei, Yosef Koronyo, Maya Koronyo-Hamaoui*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

6 Citations (Scopus)
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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 β-protein (Aβ)1–42, angiopathic Aβ1–40, non-amyloidogenic Aβ1–38, and Aβ42/Aβ40 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 Aβ burden, with one-side dominance within paired retinal and brain tissues. Importantly, OS and OD retinal Aβ 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 Aβ 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.

Original languageEnglish
Article numbere13246
Pages (from-to)1-25
Number of pages25
JournalAging Cell
Volume19
Issue number11
Early online date14 Oct 2020
DOIs
Publication statusPublished - Nov 2020

Bibliographical note

Copyright the Author(s) 2020. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.

Keywords

  • astrocytes reactivation
  • glutamine synthetase
  • myeloid cells
  • neurodegenerative disease
  • ocular proteins
  • retina
  • synaptic preservation
  • vascular amyloidosis

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