Hongsheng Zhang, Wenbing Chen, Shu Shu, Zhaoqi Dong, Wanpeng Cui, Kai Zhao, Lei Zhang, Wencheng Xiong, Lin Mei
Department of Neurosciences, School of Medicine, Case Western Reserve University, Cleveland, Ohio 44106, USA; Email:[email protected]
Alzheimer鈥檚 disease (AD) is a progressive neurodegenerative disorder that is caused by the accumulation of amyloid plaques. Formation of amyloid plaques depends on beta-amyloid (A尾) production and clearance; impaired A尾 clearance has been implicated in late-onset AD. However, underlying mechanisms are not fully understood. Here, we found that A尾 deposition was increased in 5xFAD mice lacking low-density lipoprotein receptor-related protein 4 (LRP4), a member of the LDL receptor family. Neuronal inflammation, synaptic dysfunction, and cognitive deficits in 5XFAD mice were exacerbated by LRP4 deficiency. However, Lrp4 mutation did not affect A尾 production or blood-brain barrier (BBB) integrity. LRP4 was mainly expressed in astrocyte in the brain and could interact with A尾 and ApoE. LRP4 mutant astrocytes were impaired in A尾 uptake and degradation. Together, our findings reveal a critical role for astrocytic LRP4 in A尾 metabolism and a potential pathological mechanism of AD development.