title: Hypercholesterolemia and neurodegeneration. Comparison of hippocampal phenotypes in LDLr knockout and APPswe/PS1dE9 mice.
abstract: Previous studies suggest that Alzheimer's disease (AD) neurobiology could not be explained solely by an increase in β-amyloid levels. Recently, it has been proposed that alterations in brain cholesterol metabolism may contribute to the pathogenesis of AD. In the present work, we focus on early changes in the hippocampal phenotypes of two mouse models in which cognitive impairments were previously described: a) the hypercholesterolemic LDL receptor knockout (LDLr -/-) and b) the APPswe/PS1dE9 (APP/PS1) transgenic model of familial AD. Our initial analysis, subsequent validation and additional experiments at the mRNA and protein levels demonstrate some parallels between the hippocampal phenotypes of these 2 mouse models, however our data suggest that the molecular mechanisms leading to cognitive decline are distinct in LDLr -/- and APP/PS1 animals. Genes related to cytokine signaling were significantly down-regulated in LDLr -/- mice when compared to both the wild-type and APP/PS1 mice, and these include prostaglandin-endoperoxide synthases 1 and 2 (ptgs1 and 2) and nerve grow factor (ngf). We have also detected reduced expression of genes related to lipid metabolism in LDLr -/- mice: peroxisome proliferator activated receptor gamma (pparg), pro-opiomelanocortin-alpha (pomc) and of protein kinase, AMP-activated, alpha 1 catalytic subunit of AMPK (prkaa1). Our array data also indicate that transcriptional activity of early genes involved in memory process, such as FBJ osteosarcoma oncogene (Fos) and the activity regulated cytoskeletal-associated protein (Arc) gene, are increased in the hippocampus of LDLr -/- mice. Several proteins like insulin degrading enzyme (IDE), PGC-1α, OXPHOS 1, NMDAR1 and cyclic AMP response element binding protein (CREB) are up-regulated in the LDLr -/- mice, while in the APP/PS1 mouse model only OXPHOS complexes 2, 3 and 5 are slightly downregulated. Further studies are necessary to understand the molecular pathways involved in memory loss in hypercholesterolemic LDLr -/- mice.
authors: Unitat de Farmacologia i Farmacognòsia Facultat de Farmàcia, Institut de Biomedicina (IBUB), Universitat de Barcelona, Barcelona, Spain; Biomedical Research Networking Center in Neurodegenerative Diseases (CIBERNED), Madrid, Spain.
authors: Miren
authors: M
authors: Ettcheto
authors: Unitat de Farmacologia i Farmacognòsia Facultat de Farmàcia, Institut de Biomedicina (IBUB), Universitat de Barcelona, Barcelona, Spain; Biomedical Research Networking Center in Neurodegenerative Diseases (CIBERNED), Madrid, Spain.
authors: Dmitry
authors: D
authors: Petrov
authors: Unitat de Bioquímica, Facultat de Medicina i Ciències de la Salut, Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Universitat Rovira i Virgili, C./St. Llorenç 21, 43201 Reus, Tarragona, Spain; Biomedical Research Networking Center in Neurodegenerative Diseases (CIBERNED), Madrid, Spain.
authors: Ignacio
authors: I
authors: Pedrós
authors: Unitat de Farmacologia i Farmacognòsia Facultat de Farmàcia, Institut de Biomedicina (IBUB), Universitat de Barcelona, Barcelona, Spain; Biomedical Research Networking Center in Neurodegenerative Diseases (CIBERNED), Madrid, Spain.
authors: Luisa
authors: L
authors: de Lemos
authors: Unitat de Farmacologia i Farmacognòsia Facultat de Farmàcia, Institut de Biomedicina (IBUB), Universitat de Barcelona, Barcelona, Spain; Biomedical Research Networking Center in Neurodegenerative Diseases (CIBERNED), Madrid, Spain.
authors: Mercè
authors: M
authors: Pallàs
authors: Unitat de Farmacologia i Farmacognòsia Facultat de Farmàcia, Institut de Biomedicina (IBUB), Universitat de Barcelona, Barcelona, Spain; Centro de Investigación Biomédica en Red de la Fisiopatología de la Obesidad y Nutrición, Spain.
authors: Marta
authors: M
authors: Alegret
authors: Unitat de Farmacologia i Farmacognòsia Facultat de Farmàcia, Institut de Biomedicina (IBUB), Universitat de Barcelona, Barcelona, Spain; Centro de Investigación Biomédica en Red de la Fisiopatología de la Obesidad y Nutrición, Spain.
authors: Juan Carlos
authors: JC
authors: Laguna
authors: Unitat de Bioquímica, Facultat de Medicina i Ciències de la Salut, Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Universitat Rovira i Virgili, C./St. Llorenç 21, 43201 Reus, Tarragona, Spain; Biomedical Research Networking Center in Neurodegenerative Diseases (CIBERNED), Madrid, Spain.
authors: Jaume
authors: J
authors: Folch
authors: Unitat de Farmacologia i Farmacognòsia Facultat de Farmàcia, Institut de Biomedicina (IBUB), Universitat de Barcelona, Barcelona, Spain; Biomedical Research Networking Center in Neurodegenerative Diseases (CIBERNED), Madrid, Spain; Centro de Biotecnología, Universidad Nacional de Loja, Av. Pío Jaramillo Alvarado y Reinaldo Espinosa, La Argelia, Loja, Ecuador. Electronic address: camins@ub.edu.
authors: Antoni
authors: A
authors: Camins
mesh_terms: D000544:Alzheimer Disease / Q000150:complications / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002784:Cholesterol / Q000378:metabolism*; D003072:Cognition Disorders / Q000235:genetics / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics; D006624:Hippocampus / Q000378:metabolism*; D006937:Hypercholesterolemia / Q000150:complications / Q000378:metabolism; D007339:Insulysin / Q000235:genetics; D008297:Male; D008569:Memory Disorders / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D023421:Models, Animal; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D011973:Receptors, LDL / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics
chemical_list: C492004:Creb1 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D011973:Receptors, LDL; D014157:Transcription Factors; D002784:Cholesterol; D007339:Insulysin
keywords: APP/PS1; Alzheimer's disease; Cholesterol; Hippocampus; LDLR−/−; OXPHOS