Contextualizing the Role of Osteopontin in the Inflammatory Responses of Alzheimer's Disease

Alzheimer's disease (AD) is characterized by progressive accumulations of extracellular amyloid-beta (A beta) aggregates from soluble oligomers to insoluble plaques and hyperphosphorylated intraneuronal tau, also from soluble oligomers to insoluble neurofibrillary tangles (NFTs). Tau and A beta complexes spread from the entorhinal cortex of the brain to interconnected regions, where they bind pattern recognition receptors on microglia and astroglia to trigger inflammation and neurotoxicity that ultimately lead to neurodegeneration and clinical AD. Systemic inflammation is initiated by A beta's egress into the circulation, which may be secondary to microglial activation and can confer both destructive and reparative actions. Microglial activation pathways and downstream drivers of A beta/NFT neurotoxicity, including inflammatory regulators, are primary targets for AD therapy. Osteopontin (OPN), an inflammatory cytokine and biomarker of AD, is implicated in A beta clearance and toxicity, microglial activation, and inflammation, and is considered to be a potential therapeutic target. Here, using the most relevant works from the literature, we review and contextualize the evidence for a central role of OPN and associated inflammation in AD.