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The Journal of Neuroscience, April 1, 2009, 29(13):4252-4262; doi:10.1523/JNEUROSCI.5572-08.2009

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Neurobiology of Disease
Microglia Mediate the Clearance of Soluble Aβ through Fluid Phase Macropinocytosis

Shweta Mandrekar,¹ Qingguang Jiang,¹ C. Y. Daniel Lee,¹ Jessica Koenigsknecht-Talboo,² David M. Holtzman,² and Gary E. Landreth¹

¹Alzheimer Research Laboratory, Department of Neurosciences, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, and ²Department of Neurology and Hope Center for Neurological Disorders, Washington University, St. Louis, Missouri 63110

Correspondence should be addressed to Gary E. Landreth, Alzheimer Research Laboratory, Department of Neurosciences, Case Western Reserve University School of Medicine, Cleveland, OH 44106. Email: gel2{at}cwru.edu

Alzheimer's disease is characterized by the progressive deposition of β-amyloid (Aβ) within the brain parenchyma and its subsequent accumulation into senile plaques. Pathogenesis of the disease is associated with perturbations in Aβ homeostasis and the inefficient clearance of these soluble and insoluble peptides from the brain. Microglia have been reported to mediate the clearance of fibrillar Aβ (fAβ) through receptor-mediated phagocytosis; however, their participation in clearance of soluble Aβ peptides (sAβ) is largely unknown. We report that microglia internalize sAβ 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 sAβ is dependent on both actin and tubulin dynamics and does not involve clathrin assembly, coated vesicles or membrane cholesterol. Upon internalization, fluorescently labeled sAβ 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 sAβ and fAβ 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 sAβ, the fluorescent chromophore is retained by the microglial cell. These studies identify an important mechanism through which microglial cells participate in the maintenance of Aβ homeostasis, through their capacity to constitutively clear sAβ peptides from the brain.

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Received Nov. 21, 2008; revised Feb. 5, 2009; accepted March 2, 2009.

Correspondence should be addressed to Gary E. Landreth, Alzheimer Research Laboratory, Department of Neurosciences, Case Western Reserve University School of Medicine, Cleveland, OH 44106. Email: gel2{at}cwru.edu

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