Wednesday, January 15, 2025
1/15/2025
Alzheimer’s disease (AD) is the most common cause of dementia and is a heavy burden to patients, family and society. Based on that postmortem AD brains exhibit mitochondrial dysfunction and neuroinflammation, the “mitochondrial cascade hypothesis” has been proposed that mitochondrial dysfunction plays an important role in the pathogenesis of AD. The exact mechanism of how mitochondrial dysfunction occurs are still unclear and we will investigate one critical mechanism of its regulation in vivo. Based on our new finding that O-GlcNAcase (OGA) activity is decreased in human AD brains we focus on the post-translational protein modification, O- GlcNAcylation. Importantly, this also related to the altered glucose metabolism in AD since glucose deprivation also increases this metabolism related post-translational protein modification. In this proposal we will relate neuroinflammation and AD-dependent changes in metabolism at the level of the astrocytes. These cells play an essential role in providing neurons with energy support, redox and neuroinflammation modulation. Reactive astrocytes occur early in AD pathogenesis. However, how astrocytic mitochondrial function are regulated and whether protein O-GlcNAcylation affects astrocytic mitochondrial function us unknown. Understanding this regulatory mechanism and how it responds to pharmacological manipulation of OGA activity will give new insights into the neuroinflammatory aspects of AD. Our preliminary studies in the APPNL-G-F knock-in mouse (AppKI) model which exhibits neuroinflammation, show that O-GlcNAcylation is also elevated and mitochondrial related gene expression is upregulated in a small group of reactive astrocytes while downregulated in the majority of homeostatic astrocytes. This provides us the foundation to test the hypothesis that increased O-GlcNAcylation impairs astrocytic mitochondrial function and neuroinflammation in vivo. We chose the AppKI mice in our study because 1) they do not have APP overexpression and thus avoiding non-pathologic gain of function effects of APP, 2) they exhibit progressive pathological features for plaque and gliosis, synaptic loss, and cognitive impairment, 3) O-GlcNAcylation effects on mutant APP-based neuroinflammation-related pathogenic mechanisms are needed to place the reported results on the inhibition of tau phosphorylation in broader context of AD. This is important as clinical trials with OGA inhibitors are ongoing for tauopathy, based on their ability of decrease tau phosphorylation and being considered for AD, while their effects on neuroinflammation, mitochondrial function and APP-based pathological progress are essentially unexplored. Completion of this exploratory project will provide much-needed critical data addressing the importance of O-GlcNAcylation in regulating astrocytic mitochondrial dysfunction and neuroinflammation, and provide novel insights into neurodegenerative mechanisms which help identify new metabolic targets for therapeutic development.
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