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

Chia Chen Liu, Chih Wei Tsai, Ferenc Deak, Justin Rogers, Michael Penuliar, You Me Sung, James N. Maher, Yuan Fu, Xia Li, Huaxi Xu, Steven Estus, Hyang Sook Hoe, John D. Fryer, Takahisa Kanekiyo, Guojun Bu

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Abstract

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-β. In humans, LRP6 and Wnt signaling are significantly downregulated in AD brains, likely by a mechanism that depends on amyloid-β. Our results define a critical pathway in which decreased LRP6-mediated Wnt signaling, synaptic dysfunction, and elevated Aβ synergistically accelerate AD progression and suggest that restoring LRP6-mediated Wnt signaling can be explored as a viable strategy for AD therapy.

Original languageEnglish (US)
Pages (from-to)63-77
Number of pages15
JournalNeuron
Volume84
Issue number1
DOIs
StatePublished - Oct 1 2014

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ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Liu, C. C., Tsai, C. W., Deak, F., Rogers, J., Penuliar, M., Sung, Y. M., Maher, J. N., Fu, Y., Li, X., Xu, H., Estus, S., Hoe, H. S., Fryer, J. D., Kanekiyo, T., & Bu, G. (2014). Deficiency in LRP6-Mediated Wnt Signaling Contributes to Synaptic Abnormalities and Amyloid Pathology in Alzheimer's Disease. Neuron, 84(1), 63-77. https://doi.org/10.1016/j.neuron.2014.08.048