title: Early alterations in energy metabolism in the hippocampus of APPswe/PS1dE9 mouse model of Alzheimer's disease.
abstract: The present study had focused on the behavioral phenotype and gene expression profile of molecules related to insulin receptor signaling in the hippocampus of 3 and 6 month-old APPswe/PS1dE9 (APP/PS1) transgenic mouse model of Alzheimer's disease (AD). Elevated levels of the insoluble Aβ (1-42) were detected in the brain extracts of the transgenic animals as early as 3 months of age, prior to the Aβ plaque formation (pre-plaque stage). By the early plaque stage (6 months) both the soluble and insoluble Aβ (1-40) and Aβ (1-42) peptides were detectable. We studied the expression of genes related to memory function (Arc, Fos), insulin signaling, including insulin receptor (Insr), Irs1 and Irs2, as well as genes involved in insulin growth factor pathways, such as Igf1, Igf2, Igfr and Igfbp2. We also examined the expression and protein levels of key molecules related to energy metabolism (PGC1-α, and AMPK) and mitochondrial functionality (OXPHOS, TFAM, NRF1 and NRF2). 6 month-old APP/PS1 mice demonstrated impaired cognitive ability, were glucose intolerant and showed a significant reduction in hippocampal Insr and Irs2 transcripts. Further observations also suggest alterations in key cellular energy sensors that regulate the activities of a number of metabolic enzymes through phosphorylation, such as a decrease in the Prkaa2 mRNA levels and in the pAMPK (Thr172)/Total APMK ratio. Moreover, mRNA and protein analysis reveals a significant downregulation of genes essential for mitochondrial replication and respiratory function, including PGC-1α in hippocampal extracts of APP/PS1 mice, compared to age-matched wild-type controls at 3 and 6 months of age. Overall, the findings of this study show early alterations in genes involved in insulin and energy metabolism pathways in an APP/PS1 model of AD. These changes affect the activity of key molecules like NRF1 and PGC-1α, which are involved in mitochondrial biogenesis. Our results reinforce the hypothesis that the impairments in both insulin signaling and energy metabolism precede the development of AD amyloidogenesis.
authors.affiliation: Unitats de Bioquímica i Farmacologia, Facultat de Medicina i Ciències de la Salut, Universitat Rovira i Virgili, Reus, Tarragona, Spain; Centros de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Spain; Laboratorio de Regeneración y Desarrollo Neural, Instituto de Neurobiología, Departamento de Biología Celular y Molecular, CUCBA, Mexico.
authors.forename: Ignacio
authors.initials: I
authors.lastname: Pedrós
authors.affiliation: Unitat de Farmacologia i Farmacognòsia, Facultat de Farmàcia, Institut de Biomedicina de la UB (IBUB), Universitat de Barcelona, Barcelona, Spain; Centros de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Spain; Laboratorio de Regeneración y Desarrollo Neural, Instituto de Neurobiología, Departamento de Biología Celular y Molecular, CUCBA, Mexico.
authors.forename: Dmitry
authors.initials: D
authors.lastname: Petrov
authors.affiliation: Unitat de Farmacologia i Farmacognòsia, Facultat de Farmàcia, Institut de Biomedicina de la UB (IBUB), Universitat de Barcelona, Barcelona, Spain; Centros de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Spain; Laboratorio de Regeneración y Desarrollo Neural, Instituto de Neurobiología, Departamento de Biología Celular y Molecular, CUCBA, Mexico.
authors.forename: Michael
authors.initials: M
authors.lastname: Allgaier
authors.affiliation: Unitats de Bioquímica i Farmacologia, Facultat de Medicina i Ciències de la Salut, Universitat Rovira i Virgili, Reus, Tarragona, Spain; Centros de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Spain; Laboratorio de Regeneración y Desarrollo Neural, Instituto de Neurobiología, Departamento de Biología Celular y Molecular, CUCBA, Mexico.
authors.forename: Francesc
authors.initials: F
authors.lastname: Sureda
authors.affiliation: Unitat de Farmacologia i Farmacognòsia, Facultat de Farmàcia, Institut de Biomedicina de la UB (IBUB), Universitat de Barcelona, Barcelona, Spain; Centros de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Spain; Laboratorio de Regeneración y Desarrollo Neural, Instituto de Neurobiología, Departamento de Biología Celular y Molecular, CUCBA, Mexico.
authors.forename: Emma
authors.initials: E
authors.lastname: Barroso
authors.affiliation: Department of Neurosciences, Case Western Reserve University, Cleveland OH USA; Laboratorio de Neurobiología Celular y Molecular, División de Neurociencias, CIBO, IMSS, Mexico; Laboratorio de Regeneración y Desarrollo Neural, Instituto de Neurobiología, Departamento de Biología Celular y Molecular, CUCBA, Mexico.
authors.forename: Carlos
authors.initials: C
authors.lastname: Beas-Zarate
authors.affiliation: Departament de Biologia Cellular, Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain; Laboratorio de Regeneración y Desarrollo Neural, Instituto de Neurobiología, Departamento de Biología Celular y Molecular, CUCBA, Mexico.
authors.forename: Carme
authors.initials: C
authors.lastname: Auladell
authors.affiliation: Unitat de Farmacologia i Farmacognòsia, Facultat de Farmàcia, Institut de Biomedicina de la UB (IBUB), Universitat de Barcelona, Barcelona, Spain; Centros de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Spain; Laboratorio de Regeneración y Desarrollo Neural, Instituto de Neurobiología, Departamento de Biología Celular y Molecular, CUCBA, Mexico.
authors.forename: Mercè
authors.initials: M
authors.lastname: Pallàs
authors.affiliation: Unitat de Farmacologia i Farmacognòsia, Facultat de Farmàcia, Institut de Biomedicina de la UB (IBUB), Universitat de Barcelona, Barcelona, Spain; Centros de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Spain; Laboratorio de Regeneración y Desarrollo Neural, Instituto de Neurobiología, Departamento de Biología Celular y Molecular, CUCBA, Mexico.
authors.forename: Manuel
authors.initials: M
authors.lastname: Vázquez-Carrera
authors.affiliation: Department of Neurosciences, Case Western Reserve University, Cleveland OH USA; Laboratorio de Regeneración y Desarrollo Neural, Instituto de Neurobiología, Departamento de Biología Celular y Molecular, CUCBA, Mexico.
authors.forename: Gemma
authors.initials: G
authors.lastname: Casadesús
authors.affiliation: Unitats de Bioquímica i Farmacologia, Facultat de Medicina i Ciències de la Salut, Universitat Rovira i Virgili, Reus, Tarragona, Spain; Centros de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Spain; Laboratorio de Regeneración y Desarrollo Neural, Instituto de Neurobiología, Departamento de Biología Celular y Molecular, CUCBA, Mexico.
authors.forename: Jaume
authors.initials: J
authors.lastname: Folch
authors.affiliation: Unitat de Farmacologia i Farmacognòsia, Facultat de Farmàcia, Institut de Biomedicina de la UB (IBUB), Universitat de Barcelona, Barcelona, Spain; Centros de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Spain; Laboratorio de Regeneración y Desarrollo Neural, Instituto de Neurobiología, Departamento de Biología Celular y Molecular, CUCBA, Mexico. Electronic address: camins@ub.edu.
authors.forename: Antoni
authors.initials: A
authors.lastname: Camins
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016564:Amyloid beta-Protein Precursor / Q000502:physiology*; D058227:Amyloidogenic Proteins; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D015153:Blotting, Western; D004195:Disease Models, Animal; D004734:Energy Metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D006624:Hippocampus / Q000378:metabolism* / Q000473:pathology; D007124:Immunoenzyme Techniques; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism* / Q000473:pathology; D053764:Presenilin-1 / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: C545487:APP protein, human; D016564:Amyloid beta-Protein Precursor; D058227:Amyloidogenic Proteins; D015415:Biomarkers; D053764:Presenilin-1; D012333:RNA, Messenger
keywords: APPswe/PS1dE9; Alzheimer's disease; Hippocampus; Insulin receptor; Mitochondria; Tau