Retinal ganglion cell loss and gliosis in the retinofugal projection following intravitreal exposure to amyloid-beta.

Retinal ganglion cell loss and gliosis in the retinofugal projection following intravitreal exposure to amyloid-beta.

Simons ES;Smith M A;Dengler-Crish C M;Crish SD

Neurobiology of Disease

2020

2020-10-26

Pathological accumulations of amyloid-beta (Aβ) peptide are found in retina early in Alzheimer's disease, yet its effects on retinal neuronal structure remain unknown. To investigate this, we injected fibrillized Aβ(1-42) protein into the eye of adult C57BL/6 J mice and analyzed the retina, optic nerve (ON), and the superior colliculus (SC), the primary retinal target in mice. We found that retinal Aβ exposure stimulated microglial activation and retinal ganglion cell (RGC) loss as early as 1-week post-injection. Pathology was not limited to the retina, but propagated into other areas of the central nervous system. Microgliosis spread throughout the retinal projection (retina, ON, and SC), with multiplex protein quantitation demonstrating an increase in endogenously produced Aβ in the ON and SC corresponding to the injected retinas. Surprisingly, this pathology spread to the opposite side, with unilateral Aβ eye injections driving increased Aβ levels, neuroinflammation, and RGC death in the opposite, un-injected retinal projection. As Aβ-mediated microglial activation has been shown to propagate Aβ pathology, we also investigated the role of the Aβ-binding microglial scavenger receptor CD36 in this pathology. Transgenic mice lacking the CD36 receptor were resistant to Aβ-induced inflammation and RGC death up to 2 weeks following exposure. These results indicate that Aβ pathology drives regional neuropathology in the retina and does not remain isolated to the affected eye, but spreads throughout the nervous system. Further, CD36 may serve as a promising target to prevent Aβ-mediated inflammatory damage.

Inflammation; Glaucoma; Alzheimer's disease; Retina; Superior colliculus; Amyloid-beta; CD36; Cluster of differentiation 36

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