PROJECT SUMMARY / ABSTRACT The present administrative supplement application responds to NOT-AG-20-034, “Notice of Special Interest: Alzheimer's-focused administrative supplements for NIH grants that are not focused on Alzheimer's disease”. Under the parent grant for the present administrative supplement, R01 grant 1R01EY031248-01, entitled “Novel mechanism controlling calcium signaling to treat and prevent neurodegeneration in early stage glaucoma”, we are targeting a novel signaling pathway for the development of a novel pharmacological intervention to control degeneration of nerve cells in the retina and optic nerve due to glaucoma, a major cause of visual loss and blindness in the United States and worldwide. Specifically, we plan to determine mechanisms of action and to measure preservation of neuronal viability and function in model systems of glaucoma. The proposed research of the parent award will allow us to generate preclinical data needed for the development of novel neuroprotectants to complement existing therapies targeting intraocular pressure. The research proposed under the present Alzheimer's disease (AD)-focused administrative supplement application will allow us to build on these novel preclinical data sets and thereby to develop a novel therapeutic strategy for the protection of neurons of the central nervous system (CNS) affected by AD. Specifically, we will test the hypothesis that similar to neurons of the retina and optic nerve affected by glaucoma, the lack of cellular defense mechanisms resulting from AD pathology reducing viability and function of CNS neurons can be attenuated by the novel therapeutic strategy under development in the parent award. To this end, a novel intervention approach will be developed that can be exploited to devise novel treatments that can be delivered to CNS neurons affected by AD protecting them from oxidative stress mediated damage and loss of function. Three-dimensional (3D) bio-printed human neural cell constructs will be used as in vitro models for AD and for drug discovery in AD and related dementias employing experimental strategies aligned with the parent award. The proposed experiments will determine the potential of the targeted novel therapeutic strategy for preventative and neuroprotective therapies in AD. The innovative strategy has the potential to generate a first-in-class pharmacotherapy approach for AD. The strategy's potentially high impact lies in its capacity to be both preventative and therapeutic in nature and to complement current and future treatment designs and rationales.