Acceleration of brain amyloidosis in an Alzheimer's disease mouse model by a folate, vitamin B6 and B12-deficient diet.
Epidemiological and clinical studies indicate that elevated circulating level of homocysteine (Hcy) is a risk factor for developing Alzheimer's disease (AD). Dietary deficiency of folate, vitamin B6 and B12 results in a significant increase of Hcy levels, a condition also known as hyperhomocysteinemia (HHcy). In the present study we tested the hypothesis that a diet deficient for these three important factors when administered to a mouse model of AD, i.e. Tg2576, will result in HHcy and in an acceleration of their amylodotic phenotype. Compared with Tg2576 mice on regular chow, the ones receiving the diet deficient for folate, B6 and B12 developed HHcy. This condition was associated with a significant increase in Abeta levels in the cortex and hippocampus, and an elevation of Abeta deposits in the same regions. No significant changes were observed for steady-state levels of total APP, BACE-1, ADAM-10, PS1 and nicastrin in the brains of mice with HHcy. No differences were observed for the main Abeta catabolic pathways, i.e. IDE and neprilysin proteins, or the Abeta chaperone apolipoprotein E. Our findings demonstrate that a dietary condition which leads to HHcy may also result in increased Abeta levels and deposition in a transgenic mouse model of AD-like amylodosis. They further support the concept that dietary factors can contribute to the development of AD neuropathology.
Zhuo
Jia-Min
JM
Temple University, School of Medicine, Department of Pharmacology, Philadelphia, PA 19140, USA.
Praticò
Domenico
D
D000544:Alzheimer Disease / Q000209:etiology* / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000686:Amyloidosis / Q000209:etiology*; D000818:Animals; D001921:Brain / Q000378:metabolism*; D004195:Disease Models, Animal; D005260:Female; D005494:Folic Acid Deficiency / Q000150:complications*; D006801:Humans; D020138:Hyperhomocysteinemia / Q000150:complications; D051379:Mice; D008822:Mice, Transgenic; D014806:Vitamin B 12 Deficiency / Q000150:complications*; D026681:Vitamin B 6 Deficiency / Q000150:complications*
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor