Friday, November 22, 2024
11/22/2024
PROJECT SUMMARY While dementia is considered a disease of learning and memory, early disruptions to sensory processes such as visual impairments are shown to occur prior to cognitive decline and increase risk for Alzheimer’s disease (AD) diagnosis. There is a lack of essential knowledge on the role visual sensory impairment plays in onset and progression of AD. One targeted approach to resolving this gap in knowledge requires identifying how pathological amyloid and tau protein accumulations in the eye damage the entire primary visual circuit from retina to brain. Understanding how and when dysfunction occurs along this primary retinal pathway may illuminate new opportunities for early intervention in AD. The objective of this R03 proposal is to uncover novel disease mechanisms arising from visual dysfunction that can be targeted for prevention or early dementia intervention. The central hypothesis of this research is that presence of pathological Aβ or tau in the retina causes damaging changes along the primary retinal pathway to primary visual cortex (V1), where disease mechanisms can then spread via V1’s interconnections to brain regions affecting learning and memory. Preliminary research shows that pathological amyloid and tau proteins injected in the mouse eye cause hyperactivity of neurons in V1, which can ultimately lead to neurodegeneration. This hyperactivity may result from damage to GABA interneurons in this region. We will use experimental models that induce amyloid and tau pathology into the visual system of healthy mice by injecting these proteins into the a) eye or b) V1 and measuring the effects of this manipulation on visual system circuitry in accordance with the following Specific Aims: SA1) Determine how pathological AD proteins in the eye affect structure and function of the primary visual pathway in the brain; SA2) Determine how pathological amyloid and tau proteins in primary visual cortex (V1) impact interconnected brain pathways. These studies will generate important preliminary data identifying mechanisms by which early visual system pathology may damage non-visual brain regions. This work will provide the foundation for future research addressing a critical barrier in the field of identifying targets for intervention that can protect both visual function and disease progression in AD.
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