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Early alterations in energy metabolism in the hippocampus of APPswe/PS1dE9 mouse model of Alzheimer's disease.
Biochim Biophys Acta 2014; 1842(9):1556-66BB

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+Show Affiliations

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.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.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.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.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.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.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.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.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.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.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.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.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

24887203

Citation

Pedrós, Ignacio, et al. "Early Alterations in Energy Metabolism in the Hippocampus of APPswe/PS1dE9 Mouse Model of Alzheimer's Disease." Biochimica Et Biophysica Acta, vol. 1842, no. 9, 2014, pp. 1556-66.
Pedrós I, Petrov D, Allgaier M, et al. Early alterations in energy metabolism in the hippocampus of APPswe/PS1dE9 mouse model of Alzheimer's disease. Biochim Biophys Acta. 2014;1842(9):1556-66.
Pedrós, I., Petrov, D., Allgaier, M., Sureda, F., Barroso, E., Beas-Zarate, C., ... Camins, A. (2014). Early alterations in energy metabolism in the hippocampus of APPswe/PS1dE9 mouse model of Alzheimer's disease. Biochimica Et Biophysica Acta, 1842(9), pp. 1556-66. doi:10.1016/j.bbadis.2014.05.025.
Pedrós I, et al. Early Alterations in Energy Metabolism in the Hippocampus of APPswe/PS1dE9 Mouse Model of Alzheimer's Disease. Biochim Biophys Acta. 2014;1842(9):1556-66. PubMed PMID: 24887203.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Early alterations in energy metabolism in the hippocampus of APPswe/PS1dE9 mouse model of Alzheimer's disease. AU - Pedrós,Ignacio, AU - Petrov,Dmitry, AU - Allgaier,Michael, AU - Sureda,Francesc, AU - Barroso,Emma, AU - Beas-Zarate,Carlos, AU - Auladell,Carme, AU - Pallàs,Mercè, AU - Vázquez-Carrera,Manuel, AU - Casadesús,Gemma, AU - Folch,Jaume, AU - Camins,Antoni, Y1 - 2014/06/02/ PY - 2014/02/07/received PY - 2014/05/12/revised PY - 2014/05/20/accepted PY - 2014/6/3/entrez PY - 2014/6/3/pubmed PY - 2014/9/26/medline KW - APPswe/PS1dE9 KW - Alzheimer's disease KW - Hippocampus KW - Insulin receptor KW - Mitochondria KW - Tau SP - 1556 EP - 66 JF - Biochimica et biophysica acta JO - Biochim. Biophys. Acta VL - 1842 IS - 9 N2 - 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. SN - 0006-3002 UR - https://www.unboundmedicine.com/medline/citation/24887203/Early_alterations_in_energy_metabolism_in_the_hippocampus_of_APPswe/PS1dE9_mouse_model_of_Alzheimer's_disease_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0925-4439(14)00153-7 DB - PRIME DP - Unbound Medicine ER -