Dietary deficiency increases presenilin expression, gamma-secretase activity, and Abeta levels: potentiation by ApoE genotype and alleviation by S-adenosyl methionine.
Apolipoprotein E4 (ApoE4) is a risk factor for Alzheimer's disease (AD). Whether this risk arises from a deficient function of E4 or the lack of protection provided by E2 or E3 is unclear. Previous studies demonstrate that deprivation of folate and vitamin E, coupled with dietary iron as a pro-oxidant, for 1 month displayed increased presenilin 1 (PS-1) expression, gamma-secretase, and Abeta generation in mice lacking ApoE (ApoE-/- mice). While ApoE-/- mice are a model for ApoE deficiency, they may not reflect the entire range of consequences of E4 expression. We therefore compared herein the impact of the above deficient diet on mice expressing human E2, E3, or E4. As folate deficiency is accompanied by a decrease in the major methyl donor, S-adenosyl methionine (SAM), additional mice received the deficient diet plus SAM. E2 was more protective than murine ApoE or E3 and E4. Surprisingly, PS-1 and gamma-secretase were over-expressed in E3 to the same extent as in E4 even under a complete diet, and were not alleviated by SAM supplementation. Abeta increased only in E4 mice maintained under the complete diet, and was alleviated by SAM supplementation. These findings suggest dietary compromise can potentiate latent risk factors for AD.
Chan
Amy
A
Department of Biological Sciences and Health and Clinical Sciences, Center for Cellular Neurobiology and Neurodegeneration Research, University of Massachusetts, Lowell, Massachusets 01854, USA.
Tchantchou
Flaubert
F
Rogers
Eugene J
EJ
Shea
Thomas B
TB
D000483:Alleles; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism; D004789:Enzyme Activation / Q000235:genetics; D005494:Folic Acid Deficiency / Q000178:diet therapy / Q000235:genetics; D005786:Gene Expression Regulation; D005838:Genotype; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D053764:Presenilin-1 / Q000096:biosynthesis* / Q000235:genetics; D012436:S-Adenosylmethionine / Q000008:administration & dosage* / Q000627:therapeutic use; D014811:Vitamin E Deficiency / Q000178:diet therapy / Q000235:genetics
D016229:Amyloid beta-Peptides; D001057:Apolipoproteins E; D053764:Presenilin-1; D012436:S-Adenosylmethionine; D053829:Amyloid Precursor Protein Secretases