Figure 2

Innate immune responses in the Alzheimer’s disease brain. Age-induced cerebrovascular dysfunction induces deregulation of tight junction protein expression, which compromises the integrity of the blood–brain barrier (BBB). A compromised BBB promotes the entry of blood-borne molecules within the perivascular space and brain parenchyma. Patrolling (Ly6C^low) monocytes are mobilized by inflammatory cues triggered by vascular amyloid-beta (Aβ) microaggregates, contributing to their phagocytosis. Circulating proinflammatory (Ly6C^high) monocytes are also mobilized by brain-derived inflammatory cues, adhere to brain endothelium and consequently infiltrate brain parenchyma. Aβ-induced inflammatory conditions promote the differentiation of Ly6C^high monocytes into bone marrow-derived macrophages (BMDM) that exhibit enhanced Aβ phagocytic activity. Perivascular macrophages (PM) could contribute to parenchymal Aβ deposit elimination via an efficient Aβ species clearance at the BBB. In an Aβ-induced inflammatory microenvironment, neurons (N) become stressed leading to their dysfunction and ultimately their death. Taken together, the presence of Aβ plaques, soluble Aβ species, proinflammatory molecules and blood-borne molecules constitute a stressful microenvironment that activates the quiescent microglia (QM). Amoeboid activated microglial cells can adopt two main phenotypes that coexist in Alzheimer's disease brain: M1 classically activated microglia (AM1) and M2 alternatively activated microglia (AM2). The switch between these two extreme phenotypes is influenced by age and disease progression. The AM1 phenotype is involved in Aβ phagocytosis and proinflammatory actions, such as secretion of cytokines/chemokines within the brain parenchyma. The AM2 phenotype is also involved in Aβ phagocytosis, but in contrast they have anti-inflammatory actions, including damaged tissue repair and remodeling, and cytokine/chemokine production. EC, endothelial cells.