title: Secreted and Transmembrane αKlotho Isoforms Have Different Spatio-Temporal Profiles in the Brain during Aging and Alzheimer's Disease Progression.
abstract: The Klotho protein is a β-glucuronidase, and its overexpression is associated with life extension. Its mechanism of action is not fully understood, although it has been recently reported that αKlotho improves synaptic and cognitive functions, and it may also influence a variety of structures and functions during CNS maturation and aging. The αKlotho gene has two transcripts, one encoding a transmembrane isoform (m-KL), and the other a putative secreted isoform (s-KL). Unfortunately, little is known about the secreted αKlotho isoform, since available antibodies cannot discriminate s-KL from the KL1 domain cleaved from the transmembrane isoform. This study shows, for the first time, that the klotho transcript produced by alternative splicing generates a stable protein (70 kDa), and that in contrast to the transmembrane Klotho isoform, it is ten times more abundant in the brain than in the kidney suggesting that the two isoforms may have different functions. We also studied whether klotho expression in the CNS was influenced by aging, Alzheimer's disease (AD), or a healthy lifestyle, such as voluntary moderate continuous exercise. We observed a strong correlation between high expression levels of the two klotho transcripts and the healthy status of the animals. Expression of Klotho in brain areas decayed more rapidly in the 3xTg-AD model of AD than in healthy animals, whilst moderate continuous exercise in adulthood prevents the decline in expression of both klotho transcripts.
authors.affiliation: Departament Bioquímica i Biologia Molecular, Universitat Autònoma Barcelona, Bellaterra, Spain.|Center of Animal Biotechnology and Gene Therapy (CBATEG), Universitat Autònoma Barcelona, Bellaterra, Spain.
authors.forename: Anna
authors.initials: A
authors.lastname: Massó
authors.affiliation: Departament Bioquímica i Biologia Molecular, Universitat Autònoma Barcelona, Bellaterra, Spain.|Center of Animal Biotechnology and Gene Therapy (CBATEG), Universitat Autònoma Barcelona, Bellaterra, Spain.
authors.forename: Angela
authors.initials: A
authors.lastname: Sánchez
authors.affiliation: Institut de Neurociencies, Universitat Autònoma Barcelona, Bellaterra, Spain.|Departament de Psiquiatria i Medicina Legal, Universitat Autònoma de Barcelona, Bellaterra, Spain.
authors.forename: Lydia
authors.initials: L
authors.lastname: Gimenez-Llort
authors.affiliation: Departament Bioquímica i Biologia Molecular, Universitat Autònoma Barcelona, Bellaterra, Spain.|Institut de Neurociencies, Universitat Autònoma Barcelona, Bellaterra, Spain.
authors.forename: Jose Miguel
authors.initials: JM
authors.lastname: Lizcano
authors.affiliation: Departament Bioquímica i Biologia Molecular, Universitat Autònoma Barcelona, Bellaterra, Spain.|Center of Animal Biotechnology and Gene Therapy (CBATEG), Universitat Autònoma Barcelona, Bellaterra, Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: Cañete
authors.affiliation: Departament Bioquímica i Biologia Molecular, Universitat Autònoma Barcelona, Bellaterra, Spain.|Center of Animal Biotechnology and Gene Therapy (CBATEG), Universitat Autònoma Barcelona, Bellaterra, Spain.
authors.forename: Belen
authors.initials: B
authors.lastname: García
authors.affiliation: Institut de Neurociencies, Universitat Autònoma Barcelona, Bellaterra, Spain.|Departament de Psiquiatria i Medicina Legal, Universitat Autònoma de Barcelona, Bellaterra, Spain.
authors.forename: Virginia
authors.initials: V
authors.lastname: Torres-Lista
authors.affiliation: Departament Bioquímica i Biologia Molecular, Universitat Autònoma Barcelona, Bellaterra, Spain.|Center of Animal Biotechnology and Gene Therapy (CBATEG), Universitat Autònoma Barcelona, Bellaterra, Spain.
authors.forename: Meritxell
authors.initials: M
authors.lastname: Puig
authors.affiliation: Departament Bioquímica i Biologia Molecular, Universitat Autònoma Barcelona, Bellaterra, Spain.|Center of Animal Biotechnology and Gene Therapy (CBATEG), Universitat Autònoma Barcelona, Bellaterra, Spain.
authors.forename: Assumpció
authors.initials: A
authors.lastname: Bosch
authors.affiliation: Departament Bioquímica i Biologia Molecular, Universitat Autònoma Barcelona, Bellaterra, Spain.|Center of Animal Biotechnology and Gene Therapy (CBATEG), Universitat Autònoma Barcelona, Bellaterra, Spain.|Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain.
authors.forename: Miguel
authors.initials: M
authors.lastname: Chillon
mesh_terms: D000375:Aging / Q000235:genetics / Q000378:metabolism*; D017398:Alternative Splicing / Q000235:genetics / Q000502:physiology; D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism*; D002460:Cell Line; D005260:Female; D005838:Genotype; D005966:Glucuronidase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D000090265:Klotho Proteins; D008297:Male; D051379:Mice; D016133:Polymerase Chain Reaction; D020033:Protein Isoforms / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: D020033:Protein Isoforms; D005966:Glucuronidase; D000090265:Klotho Proteins