Role of oligodendrocyte-derived IL-33 in brain aging and Alzheimer's disease

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Abstract The aged brain is thought to be more vulnerable to stresses than its young counterpart, and different in its coping with neuroinflammation and ability to repair an injury. A better understanding of the brain aging process will provide valuable information. This knowledge enables one to mitigate age-related declines in cognitive, emotional, sensory, and motor functions. Such information may also promote effective strategies for treating age-related neurodegenerative diseases, such as Alzheimer’s disease (AD). The brain is composed of multiple types of non-neuronal cells besides neurons, and each type seems to undergo unique age-related changes following its genetic program. Oligodendrocytes (OLs), a major glial cell population, form myelin sheaths, essential for rapid axonal conduction in the central nervous system (CNS). OLs also provide metabolic and nutritional support to neurons and contribute to other homeostatic regulations for axonal communication. Recently, our OL-specific transcriptomic analyses revealed that IL-33, a member of the IL-1 family known to contribute to neural circuit refining and neural repair, is increasingly expressed in OLs with age. Consequently, at one year of age, OLs become the predominant source of IL-33 (> 90% of all IL33-expressing cells) in the mouse CNS. Interestingly, IL-33 genetic variations are correlated with the risk of AD in patients, and higher levels of IL-33 in the brain significantly benefited amyloid plaque clearance in mice. Given the critical functions of IL-33, it is crucial to identify detailed cell-specific mechanisms of IL-33 in the aged brain. To understand how OL-derived IL-33 shapes brain aging and AD-like disease progression, we will employ mouse genetic tools that allow OL-specific or all CNS macroglia (OL lineage glia and astrocytes)- targeted IL-33 conditional knockout (cKO). More specifically, in Aim1, we will determine whether the loss of IL-33 expression selectively in OLs or all macroglia affects oligodendroglial integrity and regenerative features. We will also utilize single-cell transcriptomic analyses with those mice to determine how OL-derived IL-33 affects their properties and those of their neighbor cells. In Aim2, by applying the same genetic manipulations to a mouse model of AD (APP/PS1), we will determine whether OL-specific IL-33 regulates AD-like diseases and cognitive deficits, as well as microglia- mediated clearance of beta-amyloid (Ab) deposits. Finally, in Aim3, we will also overexpress IL33 in OLs or all macroglia to see if higher levels of IL33 impact OL integrity and Ab clearance. If successfully conducted, this study will advance our understanding of cell-cell interactions, especially those mediated by IL-33 in brain aging and during the progression of AD. Our results may promote the development of a therapeutic strategy with an oligodendroglia-targeted approach and identify related molecular mechanisms and targets for treating AD patients.