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Illuminating Glial Dysfunction in Alzheimer’s Disease with Optical Coherence Tomography

Award Number: K08AG080178
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 03/01/2023
PERIOD OF PERFORMANCE END DATE: 02/29/2028

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Illuminating Glial Dysfunction in Alzheimer’s Disease with Optical Coherence Tomography - PROJECT SUMMARY / ABSTRACT Clearance of amyloid beta (Aβ) is facilitated by glial cells, and impaired Aβ 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 Aβ overproduction. Functional OCT abnormalities in these mice may be caused by limitations in glial water movement, or by Aβ 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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $163,980 )
2026	2026	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR STE 300	DAVIS	CA	95618	YOLO	USA	Aging Research	000	4	1/28/2026	NON-COMPETING CONTINUATION	$163,980
														Subtotal = $163,980

Issue Date FY: 2025 ( Subtotal = $163,980 )
2025	2025	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR STE 300	DAVIS	CA	95618	YOLO	USA	Aging Research	000	3	1/15/2025	NON-COMPETING CONTINUATION	$163,980
														Subtotal = $163,980

Issue Date FY: 2024 ( Subtotal = $163,980 )
2024	2024	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR, STE 300	DAVIS	CA	95618	YOLO	USA	Aging Research	000	2	1/29/2024	NON-COMPETING CONTINUATION	$163,980
														Subtotal = $163,980

Issue Date FY: 2023 ( Subtotal = $163,980 )
2023	2023	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR, STE 300	DAVIS	CA	95618	YOLO	USA	Aging Research	000	1	2/28/2023	NEW	$163,980
														Subtotal = $163,980

Grand Total All Awards = $655,920

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Illuminating Glial Dysfunction in Alzheimer’s Disease with Optical Coherence Tomography

Award Number: K08AG080178

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 03/01/2023

PERIOD OF PERFORMANCE END DATE: 02/29/2028

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