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

Deficiency in cerebral amyloid beta-protein (A beta) clearance is implicated in the pathogenesis of the common late-onset forms of Alzheimer's disease (AD). Accumulation of misfolded A beta 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 A beta 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 A beta fibrils, and possibly soluble oligomers. In AD transgenic (ADtg) mice, monocyte ablation or inhibition of their migration into the brain exacerbated A beta pathology, while blood enrichment with monocytes and their increased recruitment to plaque lesion sites greatly diminished A beta burden. Profound neuroprotective effects in ADtg mice were further achieved through increased cerebral recruitment of myelomonocytes overexpressing A beta-degrading enzymes. This review summarizes the literature on cellular and molecular mechanisms of cerebral A beta clearance with an emphasis on the role of peripheral monocytes and macrophages in A beta removal.