Alzheimer?s disease (AD) and glaucoma are two of the most prevalent age-related neurodegenerative disorders recognized worldwide. Globally, AD is the most widespread cause of dementia and a substantial cause of death, while glaucoma is the leading cause of irreversible blindness. In glaucoma, a characteristic optic neuropathy is associated with progressive visual field defects. AD patients are 2-3 times more likely to develop glaucoma than those without AD and epidemiologic studies have also identified increased risk for glaucoma patients to develop AD. Histopathological hallmarks of AD in the brain, including amyloid beta (A?) accumulation and plaque formation; increase in hyperphosphorylated microtubule associated tau (pTau) protein and its somatodendritic mislocalization; microgliosis with microglial activation, and neuronal degeneration, have also been identified in the retina and optic nerve in AD and in glaucoma supporting observed disease associations. There is currently no cure for either disease, although treatments that lower intraocular pressure (IOP) can slow progression of vision loss glaucoma. An association between AT1 receptor blocker (ARB) therapy and reduction in AD neuropathology has been documented in a large, multi-center brain autopsy series. However, it is challenging to evaluate drug effects and tease apart shared risk for glaucoma and AD in older human populations with other age-associated co-morbidities. We will leverage data and tissues from our ongoing studies of mechanisms underlying optic nerve head gliosis and their response to ARB therapy in a translationally relevant large-animal glaucoma model to interrogate associations between ARB therapy, IOP, TGF?, and AD-like neuropathology in glaucoma. To test the hypothesis that ARB therapy will reduce AD-like pathology in glaucoma, we will conduct a systematic evaluation of histologic markers in ARB- and placebo-treated cats with glaucoma, with wt controls. Studies will include quantification of relevant cells, proteins and transcripts, such amyloid beta (A?), hyperphosphorylated tau (pTau) protein and microglial markers, and neuronal degeneration in retina, optic nerve and selected brain regions, in age-matched, placebo- and telmisartan- treated animals with spontaneous glaucoma. Success in these studies will provide mechanistic insight into glaucoma risk in AD patients and will provide a scientific foundation for future studies to develop new therapeutic strategies to slow disease progression and enhance quality of life in AD and glaucoma patients. By leveraging precious tissue resources generated by our current R01-funded project, we will generate preliminary data as a foundation for the design of longer-term mechanistic studies in which we plan to address our broader hypotheses, linking AD and glaucoma using complementary models. More specifically, results obtained in experiments funded by this administrative supplement are likely to enhance understanding of indirectly-observed ARB treatment effects in mitigating AD pathology in human subjects.
Alzheimer?s disease (AD) causes relentlessly progressive dementia and affects an estimated 1 in 8 Americans over the age of 65, while glaucoma is the leading cause of irreversible vision loss. Both diseases are currently incurable and are increasing in prevalence as the population ages. This project will examine the effect of glaucoma progression on AD pathology in the eye and brain, to provide information that could profoundly impact clinical management strategies for both AD and glaucoma patients.
