A novel role for osteopontin in macrophage-mediated amyloid-β clearance in Alzheimer’s models

Abstract

Osteopontin (OPN), a matricellular immunomodulatory cytokine highly expressed by myelomonocytic cells, is known to regulate immune cell migration, communication, and response to brain injury. Enhanced cerebral recruitment of monocytes achieved through glatiramer acetate (GA) immunization or peripheral blood enrichment with bone marrow (BM)-derived CD115 monocytes (Mo) curbs amyloid β-protein (Aβ) neuropathology and preserves cognitive function in murine models of Alzheimer's disease (ADtg mice). To elucidate the beneficial mechanisms of these immunomodulatory approaches in AD, we focused on the potential role of OPN in macrophage-mediated Aβ clearance. Here, we found extensive OPN upregulation along with reduction of vascular and parenchymal Aβ burden in cortices and hippocampi of GA-immunized ADtg mice. Treatment combining GA with blood-grafted Mo further increased OPN levels surrounding residual Aβ plaques. In brains from AD patients and ADtg mice, OPN was also elevated and predominantly expressed by infiltrating GFP- or Iba1-CD45 monocyte-derived macrophages engulfing Aβ plaques. Following GA immunization, we detected a significant increase in a subpopulation of inflammatory blood monocytes (CD115CD11bLy6C) expressing OPN, and subsequently, an elevated population of OPN-expressing CD11bLy6CCD45 monocyte/macrophages in the brains of these ADtg mice. Correlogram analyses indicate a strong linear correlation between cerebral OPN levels and macrophage infiltration, as well as a tight inverse relation between OPN and Aβ-plaque burden. In vitro studies corroborate in vivo findings by showing that GA directly upregulates OPN expression in BM-derived macrophages (MФ). Further, OPN promotes a phenotypic shift that is highly phagocytic (increased uptake of Aβ fibrils and surface scavenger receptors) and anti-inflammatory (altered cell morphology, reduced iNOS, and elevated IL-10 and Aβ-degrading enzyme MMP-9). Inhibition of OPN expression in MФ, either by siRNA, knockout (KO), or minocycline, impairs uptake of Aβ fibrils and hinders GA's neuroprotective effects on macrophage immunological profile. Addition of human recombinant OPN reverses the impaired Aβ phagocytosis in KO-MФ. This study demonstrates that OPN has an essential role in modulating macrophage immunological profile and their ability to resist pathogenic forms of Aβ.

A Consensus Proteomic Analysis of Alzheimer’s Disease Brain and Cerebrospinal Fluid Reveals Early Changes in Energy Metabolism Associated with Microglia and Astrocyte Activation

“…SPP1 has been nominated as an AD CSF biomarker in previous studies [106][107][108][109] . SPP1 is known to be involved in tissue repair 110 , and promotes phagocytosis of amyloid-β and an anti-inflammatory microglial phenotype 111,112 . It is closely associated with the CD44 receptor 113 , which is highly expressed on the surface of activated astrocytes 114 .…”

Oculo‐visual abnormalities in Parkinson's disease: Possible value as biomarkers

“…Indeed, besides more conclusive evidence for the use of OCT for early diagnosis, [231][232][233] several additional techniques to monitor ocular manifestations of Alzheimer's have been/are being developed; including assessing the neurovascular unit (oximetry, OCT-angiography, Doppler-OCT, dynamic retinal vessel analysis), 232 amyloid aggregation status and phosphorylated tau (hyperspectral imaging, confocal scanning laser ophthalmoscopy of autofluorescent or curcumin-labelled amyloid, fluorescent ligand eye-scanning system, fluorescence lifetime imaging ophthalmoscopy), and RGC apoptosis (DARC). [234][235][236][237][238][239][240][241] Furthermore, we have only just entered an era of groundbreaking imaging techniques, with novel developments such as (wide-field) OCT, fluorescent ligand eyescanning system, and fluorescence lifetime imaging ophthalmoscopy. More applications, for example, identifying specific cell types, are to be expected to further revolutionize research in neurodegenerative disease.…”

Integrated Proteomics Reveals Brain-Based Cerebrospinal Fluid Biomarkers in Asymptomatic and Symptomatic Alzheimer’s Disease

“…These strongly validated markers are bolded in Figure 6C. Among these validated targets were proteins with known connections to AD such as osteopontin (SPP1), a proinflammatory cytokine that has been linked to AD across several studies [52][53][54]. GAP43 of the validated synaptic panel has also been linked to neurodegeneration and its critical role in synaptic stability has been well-characterized [23,55].…”