Sunday, May 5, 2024
5/5/2024
ABSTRACT In responding to the PA-20-272 that calls for Alzheimer's-focused administrative supplements for NIH grants that are not focused on Alzheimer's Disease (AD), this application proposes to expand on the existing award (5 R01 EY031696-02) to the identification of novel pathogenesis and biomarkers of AD. There is, at present, no established cure or disease-modifying treatment for AD, largely due to the lack of clear understanding of the disease pathogenesis. The eyes provide a window into many aspects of brain function and health. Extensive eye-related complications have been observed in AD. These include the loss of retinal ganglion cells (RGCs) and thinning of the retinal nerve fiber layer (RNFL), the main cell type affected in glaucoma. Emerging evidence also suggests an overlap between the molecular mechanisms of glaucoma and those of AD. We recently reported a novel immune component involving systemic T cell responses underlying the pathogenesis of glaucoma, that signifies a paradigm shift concept in neurodegeneration. We demonstrated that chronic neurodegeneration in glaucoma is critically associated with the induction of systemic responses of CD4+ T helper 1 (Th1) cells specific to heat shock proteins (HSPs). Acute insults and stress to neurons, such as those associated with ischemia, injury, or elevated intraocular pressure, evoke microglial activation that initiates HSP-specific T cell responses to contribute to a prolonged phase of neuron loss. Moreover, data acquired through the current award (EY031696) showed further that not only patients with primary open angle glaucoma exhibited significantly increased frequencies of HSP-specific T cells in the peripheral blood compared to control subjects, but the HSP- specific T cell counts correlated with the thinning of RNFL. These results demonstrate the human relevance of a systemic T cell-mediated mechanism in glaucomatous neuronal damage. Accumulating evidence showed that peripherally activated CD4+ T cells could enter the CNS with an intact blood-brain-barrier. Together, these have led to the extension of our hypothesis that the similar immune mechanism involving systemic T cell responses in glaucoma is at the play to perpetuate neurodegeneration in AD. We therefore propose to expand the current studies to critically examine the roles of HSP-specific Th1 cells in animal models and human patients with AD. We will ask: (1) if mice and human patients with AD exhibit increased HSP-specific T cell frequencies in the peripheral blood compared to controls, and (2) if adoptive transfer of HSP-specific T cells taken from AD mice exacerbates AD pathology in the recipient mouse brains. The proposed studies may uncover novel insights into AD pathogenesis, and identification of peripheral blood and serum biomarkers may lead to new diagnostic method for screening individuals at risk for AD and/or monitoring disease progression.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
