title: Altered lipid composition in cortical lipid rafts occurs at early stages of sporadic Alzheimer's disease and facilitates APP/BACE1 interactions.
abstract: The presence of lipid alterations in lipid rafts from the frontal cortex in late stages of Alzheimer's disease (AD) has been recently demonstrated. Here, we have isolated and analyzed the lipid composition of lipid rafts from different brain areas from control and AD subjects at initial neuropathologic stages. We have observed that frontal cortex lipid rafts are profoundly altered in AD brains from the earliest stages of AD, namely AD I/II. These changes in the lipid matrix of lipid rafts affected both lipid classes and fatty acids and were also detected in the entorhinal cortex, but not in the cerebellum from the same subjects. Paralleling these changes, lipid rafts from AD frontal and entorhinal cortices displayed higher anisotropy for environment-sensitive probes, indicating that lipid changes in AD lipid rafts increased membrane order and viscosity in these domains. The pathophysiological consequences of these alterations in the development and progression of AD were strengthened by the significant, and specific, accumulation of β-secretase within the lipid rafts of AD subjects even at the earliest stages. Our results provide a mechanistic connection between lipid alterations in these microdomains and amyloidogenic processing of amyloid precursor protein.
authors.affiliation: Departamento de Biología Animal, Universidad de La Laguna, Tenerife, Spain.
authors.forename: Noemí
authors.initials: N
authors.lastname: Fabelo
authors.affiliation: Departamento de Biología Animal, Universidad de La Laguna, Tenerife, Spain.
authors.forename: Virginia
authors.initials: V
authors.lastname: Martín
authors.affiliation: Departamento de Fisiología, Universidad de La Laguna, Tenerife, Spain.
authors.forename: Raquel
authors.initials: R
authors.lastname: Marín
authors.affiliation: Institut de Neuropatologia, IDIBELL-Hospital Universitari de Bellvitge, Universitat de Barcelona, Spain, and CIBERNED (Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas), Spain.
authors.forename: Dolores
authors.initials: D
authors.lastname: Moreno
authors.affiliation: Institut de Neuropatologia, IDIBELL-Hospital Universitari de Bellvitge, Universitat de Barcelona, Spain, and CIBERNED (Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas), Spain.
authors.forename: Isidre
authors.initials: I
authors.lastname: Ferrer
authors.affiliation: Departamento de Biología Animal, Universidad de La Laguna, Tenerife, Spain. Electronic address: madiaz@ull.es.
authors.forename: Mario
authors.initials: M
authors.lastname: Díaz
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism*; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics*; D016282:Aspartic Acid Endopeptidases / Q000235:genetics*; D004843:Epistasis, Genetic / Q000235:genetics; D005260:Female; D005625:Frontal Lobe / Q000378:metabolism*; D006801:Humans; D050356:Lipid Metabolism / Q000235:genetics*; D008297:Male; D021962:Membrane Microdomains / Q000737:chemistry / Q000378:metabolism*; D008875:Middle Aged; D010446:Peptide Fragments / Q000378:metabolism
chemical_list: C545487:APP protein, human; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human
keywords: Alzheimer's disease; Amyloid precursor protein; Anisotropy; Docosahexaenoic acid; Entorhinal cortex; Frontal cortex; Lipid rafts; Membrane lipids; Membrane viscosity; Polyunsaturated fatty acids; β-secretase