title: APP intracellular domain is increased and soluble Abeta is reduced with diet-induced hypercholesterolemia in a transgenic mouse model of Alzheimer disease.
abstract: Cholesterol is one of multiple factors, other than familial genetic mutations, that can influence amyloid-beta peptide (Abeta) metabolism and accumulation in Alzheimer disease (AD). The effect of a high-cholesterol diet on amyloid precursor protein (APP) processing in brain has not been thoroughly studied. This study was designed to further investigate the role of cholesterol in the production of Abeta and APP intracellular domain (AICD) in 12-month-old Tg2576 transgenic mice. The mice were maintained on a high-cholesterol diet for 6 weeks. We found that diet-induced hypercholesterolemia increased the APP cytosolic fragment AICD and reduced sAPPalpha in the Tg2576 mice compared to the mice on a control basal diet. In addition, the levels of detergent-extracted Abeta40 were reduced, although no change in guanidine-extracted Abeta levels was observed. Full-length APP, alpha/betaC-terminal fragment (alpha/betaCTF), and beta-secretase (BACE) were not different in the cholesterol-fed mice compared to the control diet-fed mice. This study suggests that a high dietary cholesterol in aged mice may not only influence Abeta metabolism, but also regulate the AICD levels. AICD has a proposed role in signal transduction and apoptosis, hence modulation of AICD production could be an alternative mechanism by which cholesterol contributes to AD pathogenesis.
authors.affiliation: Department of Pathology, The University of Melbourne, Victoria, Australia.
authors.forename: Amee J
authors.initials: AJ
authors.lastname: George
authors.forename: R M Damian
authors.initials: RM
authors.lastname: Holsinger
authors.forename: Catriona A
authors.initials: CA
authors.lastname: McLean
authors.forename: Katrina M
authors.initials: KM
authors.lastname: Laughton
authors.forename: Konrad
authors.initials: K
authors.lastname: Beyreuther
authors.forename: Genevieve
authors.initials: G
authors.lastname: Evin
authors.forename: Colin L
authors.initials: CL
authors.lastname: Masters
authors.forename: Qiao-Xin
authors.initials: QX
authors.lastname: Li
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002791:Cholesterol, Dietary / Q000378:metabolism*; D005260:Female; D006937:Hypercholesterolemia / Q000235:genetics / Q000378:metabolism*; D007424:Intracellular Fluid / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D017434:Protein Structure, Tertiary; D012995:Solubility
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D002791:Cholesterol, Dietary