Osteopontin in Alzheimer's Disease: A Double‐Edged Sword in Neurodegeneration and Neuroprotection—A Systematic Review

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  FIGURE 1. PRISMA flowchart. From: Page et al. [52]. *Consider, if feasible to do so, reporting the number of records identified from each database or register searched (rather than the total number across all databases/registers). **If automation tools were used, indicate how many records were excluded by a human and how many were excluded by automation tools.

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  FIGURE 2. Neuroinflammation role of OPN in Alzheimer's disease pathology. This figure illustrates how OPN contributes to AD pathology by promoting inflammatory responses, synaptic pruning, and activating intracellular signaling pathways that lead to neuronal apoptosis. In pathological conditions such as AD, where amyloid plaques are present, microglia and PVM/PVF cells secrete OPN. As a chemoattractive cytokine, OPN recruits more activated microglia and infiltrating myeloid cells (macrophages/monocytes), which in turn secrete more OPN, exacerbating the inflammatory cascade. OPN exerts its effects through its receptors, integrin, and activating various pathways, including the complement cascade, TNF‐α, NF‐κB, and MAPK signaling pathways, all of which contribute to inflammatory responses and cell death. Additionally, by inhibiting TREM2/TAM signaling, OPN impairs the phagocytosis of amyloid‐beta. In neurons, OPN can also activate the Akt and P38 MAPK pathways, leading to apoptosis and inflammation. Also, it shows the microglia and astrocyte interaction to synaptic pruning by molecular cross talk. OPN and CD44 promote the inflammatory state of astrocytes, leading to the secretion of C1q, a…

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  FIGURE 3. Neuroprotective role of OPN in Alzheimer's disease pathology. This figure illustrates the neuroprotective mechanisms of OPN, including the enhancement of amyloid‐beta clearance through phagocytosis mediated by the TREM2/SYK signaling pathway in microglia and infiltrating macrophage‐derived monocytes. Additionally, OPN increases cerebral vascularization as a proangiogenic factor. We propose that c‐OPN, degraded by MMP‐9, exerts protective effects. Created with BioRender.com.