PROJECT SUMMARY / ABSTRACT
Clearance of amyloid beta (Aß) is facilitated by glial cells, and impaired Aß clearance is implicated in the
pathogenesis of Alzheimer’s disease (AD). A non-invasive assay of glial function could translate this knowledge
into improved health outcomes – leading to the development of new diagnostic tools and/or glia-targeted
therapies. Compared to other parts of the central nervous system (CNS), the retina is structurally simple. Within
the avascular layers the retina, where the only neuronal elements are photoreceptors, adjacent glia-rich and glia-
free layers can inform on glial health. In this project, functional responses to light in those avascular layers of the
retina will be monitored with optical coherence tomography (OCT), which is non-invasive and in current
widespread clinical use. Responses in the glia-rich and glia-free layers of the retina report on local shifts in water
content, which are foundational to glia-mediated waste clearance. For the first Aim of this project, we will compare
functional OCT measurements in patients with AD, patients with non-Alzheimer’s dementia, and healthy age-
matched adults. We hypothesize that the functional OCT abnormality in AD is disease-specific and is present at
early stages of the disease. Positive results would validate a new low-cost, non-invasive, and diagnostically
useful marker of AD. The second Aim of this project will use OCT to non-invasively measure retinal glial function
in genetic mouse models of disease. Knockout mice lacking the aquaporin 4 protein have impaired glial water
and waste clearance. Those mice will be crossed with APP/PS1 mice, a common model of AD based on Aß
overproduction. Functional OCT abnormalities in these mice may be caused by limitations in glial water
movement, or by Aß accumulation, or these features of AD may be synergistic. In vitro OCT of glial cells cultured
from those mice will clarify the glial contribution to OCT abnormalities. Positive findings from this Aim would
validate OCT as the first clinically-available tool to measure glial function, and provide a direct cell-to-mouse-to-
human translational approach for the assessment of glial function in neurodegenerative disease.
My career goal is to become an independently-funded physician-scientist studying AD and related
dementias. This mentored career development proposal builds upon my clinical experience as a fellowship-
trained dementia neurologist, and my research experience in OCT in Alzheimer’s patients as well as (non-OCT)
imaging of the rodent retina. The University of California – Davis is the ideal location for the proposed training:
The primary mentor will guide me in planning, organizing, and executing funded human research at the
institution’s NIA-funded Alzheimer’s Disease Research Center. The team of mentors and collaborators includes
experienced NIH-funded vision scientists who will provide training in advanced OCT techniques and Müller glial
cell culture. Additional UC Davis training and analytic resources leveraged by this proposal include graduate-
level coursework in vision science and the biology of neuroglia, the NIH-funded Clinical and Translational
Science Center, and the NIH-funded Mutant Mouse Regional Resource Center.