Scara1 deficiency impairs clearance of soluble amyloid-β by mononuclear phagocytes and accelerates Alzheimer’s-like disease progression

• Published in: Nature communications 2013-06, Vol.4 (1), p.2030-2030, Article 2030
• Main Authors: Frenkel, Dan, Wilkinson, Kim, Zhao, Lingzhi, Hickman, Suzanne E., Means, Terry K., Puckett, Lindsay, Farfara, Dorit, Kingery, Nathan D., Weiner, Howard L., El Khoury, Joseph
• Format: Article
• Language: English
• Subjects: 631/378/1689/1283; 692/420; Alzheimer Disease - metabolism; Alzheimer Disease - pathology; Amyloid beta-Peptides - metabolism; Animals; CD36 Antigens - metabolism; Cysteine Endopeptidases - pharmacology; Disease Progression; Drug Combinations; HEK293 Cells; Humanities and Social Sciences; Humans; Leukocytes, Mononuclear - drug effects; Leukocytes, Mononuclear - metabolism; Lipopolysaccharides - pharmacology; Macrophages - drug effects; Macrophages - metabolism; Mice; Microglia - drug effects; Microglia - metabolism; multidisciplinary; Phagocytes - drug effects; Phagocytes - metabolism; Presenilin-1 - metabolism; Proteolysis - drug effects; RNA, Small Interfering - metabolism; Scavenger Receptors, Class A - deficiency; Scavenger Receptors, Class A - metabolism; Science; Science (multidisciplinary); Solubility; Survival Analysis; Up-Regulation - drug effects
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms3030

In Alzheimer’s disease, soluble amyloid-β causes synaptic dysfunction and neuronal loss. Receptors involved in clearance of soluble amyloid-β are not known. Here we use short hairpin RNA screening and identify the scavenger receptor Scara1 as a receptor for soluble amyloid-β expressed on myeloid cells. To determine the role of Scara1 in clearance of soluble amyloid-β in vivo , we cross Scara1 null mice with PS1-APP mice, a mouse model of Alzheimer’s disease, and generate PS1-APP- Scara1- deficient mice. Scara1 deficiency markedly accelerates Aβ accumulation, leading to increased mortality. In contrast, pharmacological upregulation of Scara1 expression on mononuclear phagocytes increases Aβ clearance. This approach is a potential treatment strategy for Alzheimer’s disease. The scavenger receptor Scara1 , expressed on microglia and macrophages, binds beta amyloid aggregates. In a mouse model of Alzheimer’s disease, the authors show that Scara1 deficiency is associated with reduced clearance and increased deposition of aggregates in the brain, which results in early mortality.