Deficiency in LRP6-mediated Wnt signaling contributes to synaptic abnormalities and amyloid pathology in Alzheimer's disease

Neuron. 2014 Oct 1;84(1):63-77. doi: 10.1016/j.neuron.2014.08.048. Epub 2014 Sep 18.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Alzheimer Disease / metabolism*
  • Alzheimer Disease / pathology
  • Amyloid beta-Peptides / metabolism*
  • Animals
  • Cell Line, Tumor
  • Female
  • HEK293 Cells
  • Hippocampus / metabolism
  • Hippocampus / pathology
  • Humans
  • Low Density Lipoprotein Receptor-Related Protein-6 / deficiency*
  • Male
  • Mice
  • Mice, Knockout
  • Mice, Transgenic
  • Organ Culture Techniques
  • Synapses / metabolism*
  • Synapses / pathology
  • Wnt Signaling Pathway / physiology*


  • Amyloid beta-Peptides
  • LRP6 protein, human
  • Low Density Lipoprotein Receptor-Related Protein-6