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

Article, Other literature type English OPEN
Liu, Chia-Chen ; Tsai, Chih-Wei ; Deak, Ferenc ; Rogers, Justin ; Penuliar, Michael ; Sung, You Me ; Maher, James N. ; Fu, Yuan ; Li, Xia ; Xu, Huaxi ; Estus, Steven ; Hoe, Hyang-Sook ; Fryer, John D. ; Kanekiyo, Takahisa ; Bu, Guojun (2014)
  • Publisher: Elsevier BV
  • Journal: Neuron, volume 84, issue 1, pages 63-77 (issn: 0896-6273)
  • Related identifiers: doi: 10.1016/j.neuron.2014.08.048
  • Subject: Neuroscience(all) | Article

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 co-receptor 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 down-regulated 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 novel strategy for AD therapy.
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