Alzheimer’s disease (AD) is associated with impaired clearance of β-amyloid (Aβ) from the brain, a process normally facilitated by apolipoprotein E (apoE). ApoE expression is transcriptionally induced through the action of the nuclear receptors peroxisome proliferator–activated receptor gamma and liver X receptors in coordination with retinoid X receptors (RXRs). Oral administration of the RXR agonist bexarotene to a mouse model of AD resulted in enhanced clearance of soluble Aβ within hours in an apoE-dependent manner. Aβ plaque area was reduced more than 50% within just 72 hours. Furthermore, bexarotene stimulated the rapid reversal of cognitive, social, and olfactory deficits and improved neural circuit function. Thus, RXR activation stimulates physiological Aβ clearance mechanisms, resulting in the rapid reversal of a broad range of Aβ-induced deficits.

Alzheimer’s disease (AD), the most prominent cause of senile dementia, is clinically characterized by the extracellular deposition of β-amyloid (Aβ) and the intra-cellular neurofibrillary tangles. It has been well accepted that AD pathogenesis arises from perturbation in the homeostasis of Aβ in the brain. Aβ is normally produced at high levels in the brain and cleared in an equivalent rate. Thus, even a moderate decrease in the clearance leads to the accumulation of Aβ and subsequent amyloid deposition. Microglia are the tissue macrophages in the central nervous system (CNS) and have been shown to play major roles in internalization and degradation of Aβ. Aβ exists in the brain both in soluble and in fibrillar forms. Microglia interact with these two forms of Aβ in different ways. They take up soluble forms of Aβ through macropinocytosis and LDL receptor-related proteins (LRPs) mediated pathway. Fibrillar forms of Aβ interact with the cell surface innate immune receptor complex, initiating intracellular signaling cascades that stimulate phagocytosis. Inflammatory responses influence the activation status of microglia and subsequently regulate their ability to take up and degrade Aβ. ApoE and its receptors have been shown to play critical roles in these processes. In this review, we will explore the mechanisms that microglia utilize to clear Aβ and the effectors that modulate the processes.

Alzheimer's disease is characterized by the progressive deposition of ␤-amyloid (A␤) within the brain parenchyma and its subsequent accumulation into senile plaques. Pathogenesis of the disease is associated with perturbations in A␤ homeostasis and the inefficient clearance of these soluble and insoluble peptides from the brain. Microglia have been reported to mediate the clearance of fibrillar A␤ (fA␤) through receptor-mediated phagocytosis; however, their participation in clearance of soluble A␤ peptides (sA␤) is largely unknown. We report that microglia internalize sA␤ from the extracellular milieu through a nonsaturable, fluid phase macropinocytic mechanism that is distinct from phagocytosis and receptor-mediated endocytosis both in vitro and in vivo. The uptake of sA␤ is dependent on both actin and tubulin dynamics and does not involve clathrin assembly, coated vesicles or membrane cholesterol. Upon internalization, fluorescently labeled sA␤ colocalizes to pinocytic vesicles. Microglia rapidly traffic these soluble peptides into late endolysosomal compartments where they are subject to degradation. Additionally, we demonstrate that the uptake of sA␤ and fA␤ occurs largely through distinct mechanisms and upon internalization are segregated into separate subcellular vesicular compartments. Significantly, we found that upon proteolytic degradation of fluorescently labeled sA␤, the fluorescent chromophore is retained by the microglial cell. These studies identify an important mechanism through which microglial cells participate in the maintenance of A␤ homeostasis, through their capacity to constitutively clear sA␤ peptides from the brain.

Microglial interaction with extracellular ␤-amyloid fibrils (fA␤) is mediated through an ensemble of cell surface receptors, including the B-class scavenger receptor CD36, the ␣ 6 ␤ 1 -integrin, and the integrin-associated protein/CD47. The binding of fA␤ to this receptor complex has been shown to drive a tyrosine kinase-based signaling cascade leading to production of reactive oxygen species and stimulation of phagocytic activity; however, little is known about the intracellular signaling cascades governing the microglial response to fA␤. This study reports a direct mechanistic link between the fA␤ cell surface receptor complex and downstream signaling events responsible for NADPH oxidase activation and phagosome formation. The Vav guanine nucleotide exchange factor is tyrosine-phosphorylated in response to fA␤ peptides as a result of the engagement of the microglia fA␤ cell surface receptor complex. Coimmunoprecipitation studies demonstrate an A␤-dependent association between Vav and both Lyn and Syk kinases. The downstream target of Vav, the small GTPase Rac1, is GTPloaded in an A␤-dependent manner. Rac1 is both an essential component of the NADPH oxidase and a critical regulator of microglial phagocytosis. The direct role of Vav in fA␤-stimulated intracellular signaling cascades was established using primary microglia obtained from Vav ؊/؊ mice. Stimulation of Vav ؊/؊ microglia with fA␤ failed to generate NADPH oxidasederived reactive oxygen species and displayed a dramatically attenuated phagocytic response. These findings directly link Vav phosphorylation to the A␤-receptor complex and demonstrate that Vav activity is required for fA␤-stimulated intracellular signaling events upstream of reactive oxygen species production and phagosome formation.