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Date of Award
Arts & Sciences
Bachelor of Science
Neurovascular deficits are established early components of Alzheimer’s disease (AD) pathogenesis. In particular, amyloid-beta (Ab) deposits in brain blood vessels – known as cerebral amyloid angiopathy (CAA)—has been strongly linked to cerebrovascular dysfunction, cerebral microhemorrhage, and cognitive decline. A common effector mechanism that is widely accepted to be detrimental in AD is reactive oxygen species (ROS)-mediated damage and cell death. Past studies have suggested that CAA-laden vessels and cerebral arterioles exposed to exogenous Ab exhibit significant oxidative stress, while anti-ROS strategies have been shown to improve Ab-induced cerebrovascular (CV) impairment. The enzyme NADPH-oxidase has been identified as a key player in superoxide generation.
Our objective for this study was to evaluate the role of NADPH-oxidase in neurovascular and behavioral deficits in vivo. We employed mice deficient in Nox2, an isoform of the NADPH-oxidase catalytic subunit, in a PSAPP transgenic Alzheimer’s disease background. We assessed CV function in response to vasoactive agents via a live cranial window. In response to vasoactive agents, we found that aged PSAPP control mice exhibited significant vasomotor impairment, while PSAPP/Nox2KO mice demonstrated improved vascular function following topical application of vasodilators. To explore the mechanisms by which ROS inhibition reduces CV impairment in aged PSAPP mice, we visualized CAA and neuritic plaque loads using congophilic fibrillary amyloid dye methoxy-x34. We found that Nox2 inhibition led to no significant changes in parenchymal amyloid deposition but markedly reduced CAA deposits. Finally, we employed novel object recognition and location tasks, burrowing behavior tests, and Y-maze tests to assess behavioral performance in PSAPP mice, and observed improved spatial memory in PSAPP/Nox2KO mice compared to control mice. Taken together, these data suggest that NADPH-oxidase dependent ROS production is a key contributor to cerebrovascular impairment and has the potential to serve as a promising new therapeutic target for patients with CAA and AD.
Lin, Emily, "The Role of NADPH-oxidase in Mediating Neurovascular Damage in Alzheimer’s Disease" (2015). Undergraduate Theses—Restricted. 42.