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Samuel Crish, Ph.D.
Department of Pharmaceutical Sciences
Northeast Ohio Medical University
"Alzheimer's and the Eye: Amyloid-beta and tau in the visual system."
Aggregations of the microtubule-associated protein tau and amyloid-beta (Aβ) are common in a range of chronic neurodegenerative disorders. The mechanisms of their pathology remain unclear and even contentious as to whether different isoforms are toxic, protective, or benign. While extracellular amyloid plaques mediate damaging neuroinflammation, Aβ has also been implicated as affecting a number of neuronal processes, including axonal transport and neural signaling. On the other hand, tau pathology is hypothesized to spread throughout the nervous system by a mechanism where it is taken up by neurons, transported along the axon, and moved out of the terminal, where it “infects” the postsynaptic cell.While several excellent studies have determined some of the mechanisms and time courses of Alzheimer’s disease pathology spreading throughout the brain, these studies have limitations due to the brain’s complexity of interconnections and confounds with surgical injection of Aβ and tau. Here we use the retinocollicular projection, a simple and accessible part of the central nervous system, to study the initiation and spread of Aβ and tau pathology. We found that intravitreal injection of aggregated Aβ resulted in regionally-restricted gliosis in the superior colliculus (SC) contralateral to the injected eye as early as one week post-injection. We found that intravitreal injection of aggregated, but not unaggregated, tau produced sectorial deficits in anterograde axonal transport and neuroinflammation one to two weeks post-injection, which were followed by axonopathy and retinal ganglion cell (RGC) loss. Pathology spread to areas connected to retinorecipient structures, including the opposite SC and primary visual cortex. This spreading sectorial tauopathy required endogenous tau, as tau knockout mice did not exhibit degenerative changes in response to aggregated tau injection. In addition to supporting recent work implicating Aβ and tau in optic neuropathies such as glaucoma and early retinopathy in Alzheimer’s disease, this presents the retinofugal projection as a model system for studying neurodegenerative processes in the central nervous system.