Elucidating the Neuroinflammatory Signaling Roles of Heme in Alzheimer's Disease Environments

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Sankar, Sitara Bala
Wood, Levi B.
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The prevalence of Alzheimer’s disease (AD) is rapidly increasing, yet there are currently no effective therapies to halt or slow disease progression. In light of the vast failures of therapies targeting traditional AD hallmarks, such as amyloid beta (Aβ), it is becoming increasingly recognized that a combination of many complex pathological events, including neuroinflammation, contributes to AD. Thus, it is necessary to pursue novel therapeutic strategies to address multiple pathological aspects of AD. Recent findings of vascular permeability early in AD implicate blood-derived factors in AD pathology. Indeed, hemoglobin (Hb) and its co-factor, heme, are upregulated in AD brain tissue and physically bind Aβ, suggesting a role for these molecules in AD pathogenesis. However, to date there is little understanding of how these factors affect disease progression. Although less appreciated than their roles in oxygen transport, heme and Hb have potent immunomodulatory signaling functions, but these functions have not been established in the context of the brain immune cells, astrocytes and microglia. Given the importance of neuroinflammation to AD pathology, the objective of this work is to elucidate the contribution of heme to neuroinflammatory signaling in AD environments. The present work accomplishes this by using in vitro and in vivo models to determine the effects of heme, Hb, and their interactions with Aβ on glial immune function and to interrogate heme-mediated intracellular signaling mechanisms. Our findings suggest that heme and Hb suppress a myriad of critical glial immune functions, including cytokine expression, expression of scavenger receptors, and clearance of Aβ. Furthermore, we found that heme exerts these effects through modulation of the PI3K/AKT/mTOR signaling pathway. This work is the first to identify mechanisms through which heme contributes to glial dysfunction in AD environments and suggests that heme could serve as a novel therapeutic target for AD.
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