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.
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA; Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, College of Medicine, Xiamen University, Xiamen, Fujian, China.
authors.forename: Chia-Chen
authors.initials: CC
authors.lastname: Liu
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA.
authors.forename: Chih-Wei
authors.initials: CW
authors.lastname: Tsai
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA; Reynolds Oklahoma Center on Aging, Department of Geriatric Medicine, University of Oklahoma HSC, Oklahoma City, OK 73104, USA.
authors.forename: Ferenc
authors.initials: F
authors.lastname: Deak
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA.
authors.forename: Justin
authors.initials: J
authors.lastname: Rogers
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Penuliar
authors.affiliation: Department of Neuroscience, Georgetown University, Washington, D.C. 20057, USA.
authors.forename: You Me
authors.initials: YM
authors.lastname: Sung
authors.affiliation: Department of Neuroscience, Georgetown University, Washington, D.C. 20057, USA.
authors.forename: James N
authors.initials: JN
authors.lastname: Maher
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Fu
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA.
authors.forename: Xia
authors.initials: X
authors.lastname: Li
authors.affiliation: Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, College of Medicine, Xiamen University, Xiamen, Fujian, China.
authors.forename: Huaxi
authors.initials: H
authors.lastname: Xu
authors.affiliation: Department of Physiology and Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY 40506, USA.
authors.forename: Steven
authors.initials: S
authors.lastname: Estus
authors.affiliation: Department of Neuroscience, Georgetown University, Washington, D.C. 20057, USA; Convergence Brain Research Department, Korea Brain Research Institute (KBRI), 425, Jungang-daero, Jung-gu, Daegu, Korea.
authors.forename: Hyang-Sook
authors.initials: HS
authors.lastname: Hoe
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA; Neurobiology of Disease Graduate Program, Mayo Clinic College of Medicine, Jacksonville, FL 32224, USA.
authors.forename: John D
authors.initials: JD
authors.lastname: Fryer
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA.
authors.forename: Takahisa
authors.initials: T
authors.lastname: Kanekiyo
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA; Neurobiology of Disease Graduate Program, Mayo Clinic College of Medicine, Jacksonville, FL 32224, USA; Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, College of Medicine, Xiamen University, Xiamen, Fujian, China. Electronic address: bu.guojun@mayo.edu.
authors.forename: Guojun
authors.initials: G
authors.lastname: Bu
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D045744:Cell Line, Tumor; D005260:Female; D057809:HEK293 Cells; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology; D006801:Humans; D060488:Low Density Lipoprotein Receptor-Related Protein-6 / Q000172:deficiency*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009924:Organ Culture Techniques; D013569:Synapses / Q000378:metabolism* / Q000473:pathology; D060449:Wnt Signaling Pathway / Q000502:physiology*
chemical_list: D016229:Amyloid beta-Peptides; C555475:LRP6 protein, human; D060488:Low Density Lipoprotein Receptor-Related Protein-6