Clearance of cerebral Aβ in Alzheimer's disease: reassessing the role of microglia and monocytes

Abstract

Deficiency in cerebral amyloid β-protein (Aβ) clearance is implicated in the pathogenesis of the common late-onset forms of Alzheimer's disease (AD). Accumulation of misfolded Aβ in the brain is believed to be a net result of imbalance between its production and removal. This in turn may trigger neuroinflammation, progressive synaptic loss, and ultimately cognitive decline. Clearance of cerebral Aβ is a complex process mediated by various systems and cell types, including vascular transport across the blood-brain barrier, glymphatic drainage, and engulfment and degradation by resident microglia and infiltrating innate immune cells. Recent studies have highlighted a new, unexpected role for peripheral monocytes and macrophages in restricting cerebral Aβ fibrils, and possibly soluble oligomers. In AD transgenic (ADtg) mice, monocyte ablation or inhibition of their migration into the brain exacerbated Aβ pathology, while blood enrichment with monocytes and their increased recruitment to plaque lesion sites greatly diminished Aβ burden. Profound neuroprotective effects in ADtg mice were further achieved through increased cerebral recruitment of myelomonocytes overexpressing Aβ-degrading enzymes. This review summarizes the literature on cellular and molecular mechanisms of cerebral Aβ clearance with an emphasis on the role of peripheral monocytes and macrophages in Aβ removal.

Keywords: Amyloid-β protein; Aβ-degrading enzymes; Innate immune cells; Myelomonocytes; Neurodegenerative diseases; Phagocytosis.

Fig. 1

Cerebral Aβ clearance by peripheral monocyte-derived macrophages. a ADtg mice were immunized with dendritic cells (DCs) pulsed with an altered myelin-derived peptide (MOG45D). Brain-resident microglia (MG, Iba1⁺/CD45^int-low), and moreover, blood-borne infiltrating Iba1⁺/CD45^high macrophages (MΦ, red), are involved in the uptake of cerebral Aβ (4G8⁺; bright white areas), as shown in the hippocampal region from an immunized ADtg mouse. Image adopted from Koronyo-Hamaoui et al., J Neurochemistry [148]. b Phagocytosis of fibrillar Aβ₄₂ (6E10) and co-localization within CD163⁺CD36^high bone marrow-derived macrophages in cultures treated with glatiramer acetate (GA). c A GA-immunized ADtg mouse brain exhibiting increased expression of Aβ-degrading enzyme (MMP-9) by recruited blood-borne MΦ surrounding Aβ plaques. Microscopic images from Koronyo et al., Brain, [144]