@article{223f42f6f9a94bfca63ad666bfa20c5f,
title = "Deficiency in LRP6-Mediated Wnt Signaling Contributes to Synaptic Abnormalities and Amyloid Pathology in Alzheimer's Disease",
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.",
author = "Liu, {Chia Chen} and Tsai, {Chih Wei} and Ferenc Deak and Justin Rogers and Michael Penuliar and Sung, {You Me} and Maher, {James N.} and Yuan Fu and Xia Li and Huaxi Xu and Steven Estus and Hoe, {Hyang Sook} and Fryer, {John D.} and Takahisa Kanekiyo and Guojun Bu",
note = "Funding Information: This work was supported by NIH grants R01AG027924, R01AG035355, R01AG046205, P01AG030128, and P01NS074969, grants from the Alzheimer{\textquoteright}s Association, and Cure Alzheimer{\textquoteright}s Fund (to G.B.); from Mayo Clinic CRM Career Development Award and NIRG from the Alzheimer{\textquoteright}s Association (to T.K.); and from the GHR Foundation (to F.D). We thank Dr. Bart Williams (Van Andel Research Institute) for providing Lrp6 flox/flox mice; Dr. Joy Snider, Dr. Mingjie Li, and Nada Husic from the Viral Vectors Core (Washington University) for producing the lentiviruses; Lester Manly for assistance of dendritic spine counting; Dr. Jaekwang Kim for providing LDLR siRNA; and Dr. Bob Weinberg (Whitehead Institute, Cambridge) for providing β-catenin deltaN90 plasmid. We are grateful to Dr. Dennis Dickson, Monica Castanedes Casey, Linda Rousseau, and Virginia Phillips for histology and immunohistochemical analyses; Dr. Terrone Rosenberry and Dr. William Tay for advice and assistance with Aβ oligomer preparation; and Dr. Melissa Murray for developing algorithms in ImageScope software to quantify immunohistochemical staining. We also thank Caroline Stetler, Melissa Wren, and Caroline Casey for careful reading of this manuscript. Publisher Copyright: {\textcopyright} 2014 Elsevier Inc.",
year = "2014",
month = oct,
day = "1",
doi = "10.1016/j.neuron.2014.08.048",
language = "English (US)",
volume = "84",
pages = "63--77",
journal = "Neuron",
issn = "0896-6273",
publisher = "Cell Press",
number = "1",
}