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

doi:10.1111/acel.13246

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

Aging Cell. 2020 Oct 14;19(11):e13246. doi: 10.1111/acel.13246. Online ahead of print.

Authors

Jonah Doustar¹, Altan Rentsendorj¹, Tania Torbati^{1

2}, Giovanna C Regis¹, Dieu-Trang Fuchs¹, Julia Sheyn¹, Nazanin Mirzaei¹, Stuart L Graham^{3

4}, Prediman K Shah⁵, Mitra Mastali^{6

7}, Jennifer E Van Eyk^{6

8

9}, Keith L Black¹, Vivek K Gupta¹⁰, Mehdi Mirzaei^{3

10

11}, Yosef Koronyo¹, Maya Koronyo-Hamaoui^{1

6}

Affiliations

¹ Department of Neurosurgery, Cedars-Sinai Medical Center, Maxine Dunitz Neurosurgical Research Institute, Los Angeles, CA, USA.
² College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, CA, USA.
³ Department of Clinical Medicine, Macquarie University, Sydney, NSW, Australia.
⁴ Save Sight Institute, Sydney University, Sydney, NSW, Australia.
⁵ Oppenheimer Atherosclerosis Research Center, Cedars-Sinai Heart Institute, Los Angeles, CA, USA.
⁶ Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
⁷ Cedars-Sinai Medical Center, Smidt Heart Institute, Los Angeles, CA, USA.
⁸ Barbara Streisand Women's Heart Center, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
⁹ Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
¹⁰ Department of Molecular Sciences, Macquarie University, Sydney, NSW, Australia.
¹¹ Australian Proteome Analysis Facility, Macquarie University, Sydney, NSW, Australia.

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 (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 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.

Keywords: astrocytes reactivation; glutamine synthetase; myeloid cells; neurodegenerative disease; ocular proteins; retina; synaptic preservation; vascular amyloidosis.

Abstract

Grants and funding