title: Increased susceptibility of dyslipidemic LSR+/- mice to amyloid stress is associated with changes in cortical cholesterol levels.
abstract: Alzheimer's disease (AD) is a neurodegenerative disease that has been linked to changes in cholesterol metabolism. Neuronal cholesterol content significantly influences the pro-apoptotic effect of amyloid-β peptide42 (Aβ42), which plays a key role in AD development. We previously reported that aged mice with reduced expression of the lipolysis stimulated lipoprotein receptor (LSR+/-), demonstrate membrane cholesterol accumulation and decreased intracellular lipid droplets in several brain regions, suggesting a potential role of LSR in brain cholesterol distribution. We questioned if these changes rendered the LSR+/- mouse more susceptible to Aβ42-induced cognitive and biochemical changes. Results revealed that intracerebroventricular injection of oligomeric Aβ42 in male 15-month old LSR+/+ and LSR+/- mice led to impairment in learning and long-term memory and decreased cortical cholesterol content of both groups; these effects were significantly amplified in the Aβ42-injected LSR+/- group. Total latency of the Morris test was significantly and negatively correlated with cortical cholesterol content of the LSR+/- mice, but not of controls. Significantly lower cortical PSD95 and SNAP-25 levels were detected in Aβ42-injected LSR+/- mice as compared to Aβ42-injected LSR+/+ mice. In addition, 24S-hydroxy cholesterol metabolite levels were significantly higher in the cortex of LSR+/- mice. Taken together, these results suggest that changes in cortex cholesterol regulation as a result of the LSR+/- genotype were linked to increased susceptibility to amyloid stress, and we would therefore propose the aged LSR+/- mouse as a new model for understanding the link between modified cholesterol regulation as a risk factor for AD.
authors.affiliation: Université de Lorraine, UR AFPA, EA3998, Vandœuvre-lès-Nancy, Frace INRA, UR AFPA, USC 0340 INRA, Vandœuvre-lès-Nancy, France.
authors.forename: Anthony
authors.initials: A
authors.lastname: Pinçon
authors.affiliation: Université de Lorraine, UR AFPA, EA3998, Vandœuvre-lès-Nancy, Frace INRA, UR AFPA, USC 0340 INRA, Vandœuvre-lès-Nancy, France.
authors.forename: Mélanie H
authors.initials: MH
authors.lastname: Thomas
authors.affiliation: Université de Lorraine, UR AFPA, EA3998, Vandœuvre-lès-Nancy, Frace INRA, UR AFPA, USC 0340 INRA, Vandœuvre-lès-Nancy, France.
authors.forename: Marion
authors.initials: M
authors.lastname: Huguet
authors.affiliation: Université de Lorraine, UR AFPA, EA3998, Vandœuvre-lès-Nancy, Frace INRA, UR AFPA, USC 0340 INRA, Vandœuvre-lès-Nancy, France INSERM, Vandœuvre-lès-Nancy, France.
authors.forename: Ahmad
authors.initials: A
authors.lastname: Allouche
authors.affiliation: Université de Lorraine, UR AFPA, EA3998, Vandœuvre-lès-Nancy, Frace INRA, UR AFPA, USC 0340 INRA, Vandœuvre-lès-Nancy, France.
authors.forename: Julie C
authors.initials: JC
authors.lastname: Colin
authors.affiliation: Université de Lorraine, LARSA, IUT-NB, Vandoeuvre-lès-Nancy, France.
authors.forename: Alain
authors.initials: A
authors.lastname: Georges
authors.affiliation: Université de Lorraine, UR AFPA, EA3998, Vandœuvre-lès-Nancy, Frace INRA, UR AFPA, USC 0340 INRA, Vandœuvre-lès-Nancy, France.
authors.forename: Annabelle
authors.initials: A
authors.lastname: Derrien
authors.affiliation: Université de Lorraine, UR AFPA, EA3998, Vandœuvre-lès-Nancy, Frace INRA, UR AFPA, USC 0340 INRA, Vandœuvre-lès-Nancy, France.
authors.forename: Marie-Claire
authors.initials: MC
authors.lastname: Lanhers
authors.affiliation: Université de Lorraine, UR AFPA, EA3998, Vandœuvre-lès-Nancy, Frace INRA, UR AFPA, USC 0340 INRA, Vandœuvre-lès-Nancy, France Biochemistry Department, CHU de Nancy, Nancy, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Malaplate-Armand
authors.affiliation: Université de Lorraine, UR AFPA, EA3998, Vandœuvre-lès-Nancy, Frace INRA, UR AFPA, USC 0340 INRA, Vandœuvre-lès-Nancy, France.
authors.forename: Thierry
authors.initials: T
authors.lastname: Oster
authors.affiliation: Université de Lorraine, UR AFPA, EA3998, Vandœuvre-lès-Nancy, Frace INRA, UR AFPA, USC 0340 INRA, Vandœuvre-lès-Nancy, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Corbier
authors.affiliation: INSERM, Vandœuvre-lès-Nancy, France.
authors.forename: Thierry
authors.initials: T
authors.lastname: Pillot
authors.affiliation: Université de Lorraine, UR AFPA, EA3998, Vandœuvre-lès-Nancy, Frace INRA, UR AFPA, USC 0340 INRA, Vandœuvre-lès-Nancy, France Biochemistry Department, CHU de Nancy, Nancy, France.
authors.forename: Jean Luc
authors.initials: JL
authors.lastname: Olivier
authors.affiliation: Université de Lorraine, UR AFPA, EA3998, Vandœuvre-lès-Nancy, Frace INRA, UR AFPA, USC 0340 INRA, Vandœuvre-lès-Nancy, France INSERM, Vandœuvre-lès-Nancy, France.
authors.forename: Frances T
authors.initials: FT
authors.lastname: Yen
mesh_terms: D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000704:Analysis of Variance; D000818:Animals; D002540:Cerebral Cortex / Q000187:drug effects* / Q000378:metabolism*; D002784:Cholesterol / Q000378:metabolism*; D000076122:Disks Large Homolog 4 Protein; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D051528:Guanylate Kinases / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D006888:Hydroxycholesterols / Q000378:metabolism; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010446:Peptide Fragments / Q000494:pharmacology*; D012333:RNA, Messenger; D018110:Receptors, Lipoprotein / Q000172:deficiency* / Q000235:genetics; D012044:Regression Analysis; D050825:Synaptosomal-Associated Protein 25 / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D002784:Cholesterol; D000076122:Disks Large Homolog 4 Protein; D051528:Guanylate Kinases; D006888:Hydroxycholesterols; D008565:Membrane Proteins; D010446:Peptide Fragments; D012333:RNA, Messenger; D018110:Receptors, Lipoprotein; D050825:Synaptosomal-Associated Protein 25; C501447:Dlg4 protein, mouse; C494209:Snap25 protein, mouse; C075222:amyloid beta-protein (1-42); C000592022:LSR protein, mouse; C044563:24-hydroxycholesterol
keywords: Alzheimer's disease; amyloid-β oligomers; animal model; cholesterol; cognitive impairment; learning; lipolysis stimulated lipoprotein receptor; memory