Deficiency in LRP6-Mediated Wnt Signaling Contributes to Synaptic Abnormalities and Amyloid Pathology in Alzheimer's Disease

被引:180
作者
Liu, Chia-Chen [1 ,5 ]
Tsai, Chih-Wei [1 ]
Deak, Ferenc [1 ,7 ]
Rogers, Justin [1 ]
Penuliar, Michael [1 ]
Sung, You Me [6 ]
Maher, James N. [6 ]
Fu, Yuan [1 ]
Li, Xia [1 ]
Xu, Huaxi [5 ]
Estus, Steven [2 ,3 ]
Hoe, Hyang-Sook [6 ,8 ]
Fryer, John D. [1 ,4 ]
Kanekiyo, Takahisa [1 ]
Bu, Guojun [1 ,4 ,5 ]
机构
[1] Mayo Clin, Dept Neurosci, Jacksonville, FL 32224 USA
[2] Univ Kentucky, Dept Physiol, Lexington, KY 40506 USA
[3] Univ Kentucky, Sanders Brown Ctr Aging, Lexington, KY 40506 USA
[4] Mayo Clin, Coll Med, Neurobiol Dis Grad Program, Jacksonville, FL 32224 USA
[5] Xiamen Univ, Fujian Prov Key Lab Neurodegenerat Dis & Aging Re, Inst Neurosci, Xiamen, Fujian, Peoples R China
[6] Georgetown Univ, Dept Neurosci, Washington, DC 20057 USA
[7] Univ Oklahoma HSC, Dept Geriatr Med, Reynolds Oklahoma Ctr Aging, Oklahoma City, OK 73104 USA
[8] KBRI, Convergence Brain Res Dept, Taegu, South Korea
关键词
COMMON GENETIC-VARIATION; BETA-CATENIN; LRP6; RECEPTOR; PROTEIN; LOW-DENSITY-LIPOPROTEIN-RECEPTOR-RELATED-PROTEIN-6; DEGENERATION; TRANSMISSION; DYSFUNCTION; GENERATION;
D O I
10.1016/j.neuron.2014.08.048
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
Alzheimer's disease (AD) is an age-related neurological disorder characterized by synaptic loss and dementia. The low-density lipoprotein receptor-related protein 6 (LRP6) is an essential coreceptor for Wnt signaling, and its genetic variants have been linked to AD risk. Here we report that neuronal LRP6-mediated Wnt signaling is critical for synaptic function and cognition. Conditional deletion of Lrp6 gene in mouse forebrain neurons leads to age-dependent deficits in synaptic integrity and memory. Neuronal LRP6 deficiency in an amyloid mouse model also leads to exacerbated amyloid pathology due to increased APP processing to amyloid-beta. In humans, LRP6 and Wnt signaling are significantly downregulated in AD brains, likely by a mechanism that depends on amyloid-b. Our results define a critical pathway in which decreased LRP6-mediated Wnt signaling, synaptic dysfunction, and elevated Ab synergistically accelerate AD progression and suggest that restoring LRP6-mediated Wnt signaling can be explored as a viable strategy for AD therapy.
引用
收藏
页码:63 / 77
页数:15
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