Open AccessParallels between retinal and brain pathology and response to immunotherapy in old, late‐stage Alzheimer's disease mouse models
Author(s) -
Doustar Jonah,
Rentsendorj Altan,
Torbati Tania,
Regis Giovanna C.,
Fuchs DieuTrang,
Sheyn Julia,
Mirzaei Nazanin,
Graham Stuart L.,
Shah Prediman K.,
Mastali Mitra,
Van Eyk Jennifer E.,
Black Keith L.,
Gupta Vivek K.,
Mirzaei Mehdi,
Koronyo Yosef,
KoronyoHamaoui Maya
Publication year - 2020
Publication title -
aging cell
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.103
H-Index - 140
eISSN - 1474-9726
pISSN - 1474-9718
DOI - 10.1111/acel.13246
Subject(s) - retinal , retina , biology , pathology , disease , neuroscience , astrocytosis , immunology , medicine , central nervous system , biochemistry
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 (APP SWE /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 Aβ 1–40 , non‐amyloidogenic Aβ 1–38 , and Aβ 42 /Aβ 40 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.