Mechanism mediating oligomeric Aβ clearance by naïve primary microglia

Neurobiology of Disease

Chi-Yuan Cho¹  Pei-Hao Chen²  Feng-Shiun Shie³  Fong-Lee Huang⁴  Bo-Shen Guo⁴  Huey-Jen Tsay⁵  Cheng-Ning Yang⁵  Yi-Jen Chen⁵  Young-Ji Shiao⁶ 

[1] Department of Life Sciences and Institute of Genome Sciences, National Yang-Ming University, Taipei 11221, Taiwan;Department of Neurology, Mackay Memorial Hospital, Mackay Medicine, Nursing and Management College, Taipei, Taiwan;Division of Mental Health and Addiction Medicine, National Health Research Institute, Zhunan 35053, Taiwan;Institute of Anatomy and Cell Biology, National Yang-Ming University, Taipei 11221, Taiwan;Institute of Neuroscience, School of Life Science and Brain Research Center, National Yang-Ming University, 155, Li-Nung Street, Section 2, Taipei 11221, Taiwan;National Research Institute of Chinese Medicine, Taipei 11221, Taiwan;

关键词: Beta-amyloid;    Alzheimer's disease;    Scavenger receptors;    Lysosomal degradation;   

DOI  :  

来源: DOAJ

【 摘 要 】

The accumulation of soluble oligomeric amyloid-β peptide (oAβ) proceeds the formation of senile plaques and contributes to synaptic and memory deficits in Alzheimer's disease (AD). The mechanism of mediating microglial oAβ clearance remains unclear and thought to occur via scavenger receptors (SRs) in microglia. SRs respond to their ligands in a subtype-specific manner. Therefore, we sought to identify the specific subtypes of SRs that mediate oAβ internalization and proteases that degrade oAβ species in naïve primary microglia. The component of oAβ species were characterized by western blot analysis, analytical ultracentrifugation analysis, and atomic force microscopy. The oAβ species remained soluble in the medium and microglial lysates during incubation at 37 °C. SR-A, but not CD36, mediated oAβ internalization in microglia as suggested by the use of subtype-specific neutralizing antibodies and small interfering RNAs (siRNAs). Immunoprecipitation analysis showed that oAβ interacted with SR-A on the plasma membrane. After internalization, over 40% of oAβ vesicles were trafficked toward lysosomes and degraded by cysteine proteases, including cathepsin B. The inhibitors of proteasome, neprilysin, matrix metalloproteinases, and insulin degrading enzyme failed to protect internalized oAβ from degradation. Our study suggests that SR-A and lysosomal cathepsin B are critical in microglial oAβ clearance, providing insight into how microglia are involved in the clearance of oAβ and their roles in the early stages of AD.

【 授权许可】

Unknown