Neurodegeneration: Zhang et al.

Lack of LRP4 in astrocyte enhances beta-amyloid deposition in 5XFAD mice

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;

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that is caused by the accumulation of amyloid plaques. Formation of amyloid plaques depends on beta-amyloid (Aβ) production and clearance; impaired Aβ clearance has been implicated in late-onset AD. However, underlying mechanisms are not fully understood. Here, we found that Aβ 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 Aβ production or blood-brain barrier (BBB) integrity. LRP4 was mainly expressed in astrocyte in the brain and could interact with Aβ and ApoE. LRP4 mutant astrocytes were impaired in Aβ uptake and degradation. Together, our findings reveal a critical role for astrocytic LRP4 in Aβ metabolism and a potential pathological mechanism of AD development.