title: Identification of plexin A4 as a novel clusterin receptor links two Alzheimer's disease risk genes.
abstract: Although abundant genetic and biochemical evidence strongly links Clusterin (CLU) to Alzheimer disease (AD) pathogenesis, the receptor for CLU within the adult brain is currently unknown. Using unbiased approaches, we identified Plexin A4 (PLXNA4) as a novel, high-affinity receptor for CLU in the adult brain. PLXNA4 protein expression was high in brain with much lower levels in peripheral organs. CLU protein levels were significantly elevated in the cerebrospinal fluid (CSF) of Plxna4-/-mice and, in humans, CSF levels of CLU were also associated with PLXNA4 genotype. Human AD brains had significantly increased the levels of CLU protein but decreased levels of PLXNA4 by ∼50%. To determine whether PLXNA4 levels influenced cognition, we analyzed the behaviour of Plxna4+/+, Plxna4+/-, and Plxna4-/-mice. In comparison to WT controls, both Plxna4+/-and Plxna4-/-mice were hyperactive in the open field assay while Plxna4-/-mice displayed a hyper-exploratory (low-anxiety phenotype) in the elevated plus maze. Importantly, both Plxna4+/-and Plxna4-/-mice displayed prominent deficits in learning and memory in the contextual fear-conditioning paradigm. Thus, even a 50% reduction in the level of PLXNA4 is sufficient to cause memory impairments, raising the possibility that memory problems seen in AD patients could be due to reductions in the level of PLXNA4. Both CLU and PLXNA4 have been genetically associated with AD risk and our data thus provide a direct relationship between two AD risk genes. Our data suggest that increasing the levels of PLXNA4 or targeting CLU-PLXNA4 interactions may have therapeutic value in AD.
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, FL, SA.
authors.forename: Silvia S
authors.initials: SS
authors.lastname: Kang
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, FL, SA.
authors.forename: Aishe
authors.initials: A
authors.lastname: Kurti
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, FL, SA.|Neurobiology of Disease Graduate Program, Mayo Clinic College of Medicine, Jacksonville, FL.
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Wojtas
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, FL, SA.
authors.forename: Kelsey E
authors.initials: KE
authors.lastname: Baker
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, FL, SA.
authors.forename: Chia-Chen
authors.initials: CC
authors.lastname: Liu
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, FL, SA.
authors.forename: Takahisa
authors.initials: T
authors.lastname: Kanekiyo
authors.affiliation: Department of Psychiatry and Hope Center, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: Yuetiva
authors.initials: Y
authors.lastname: Deming
authors.affiliation: Department of Psychiatry and Hope Center, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: Carlos
authors.initials: C
authors.lastname: Cruchaga
authors.affiliation: Sanders-Brown Center on Aging, Department of Physiology, University of Kentucky, Lexington, KY, USA.
authors.forename: Steven
authors.initials: S
authors.lastname: Estus
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, FL, SA.|Neurobiology of Disease Graduate Program, Mayo Clinic College of Medicine, Jacksonville, FL.
authors.forename: Guojun
authors.initials: G
authors.lastname: Bu
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, FL, SA fryer.john@mayo.edu.|Neurobiology of Disease Graduate Program, Mayo Clinic College of Medicine, Jacksonville, FL.
authors.forename: John D
authors.initials: JD
authors.lastname: Fryer
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics* / Q000503:physiopathology; D000818:Animals; D051152:Clusterin / Q000096:biosynthesis / Q000235:genetics*; D003071:Cognition / Q000502:physiology; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008568:Memory / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D020641:Polymorphism, Single Nucleotide; D060066:Protein Interaction Maps / Q000235:genetics*; D011956:Receptors, Cell Surface / Q000096:biosynthesis / Q000235:genetics*; D012307:Risk Factors
chemical_list: C495242:CLU protein, human; D051152:Clusterin; C524474:Plxna4 protein, human; D011956:Receptors, Cell Surface