Hyperhomocysteinemia in Alzheimer's disease: the hen and the egg? (original) (raw)

Journal of Alzheimer's Disease xx (20xx) x-xx Abstract. Hyperhomocysteinemia is associated with Alzheimer's disease (AD). The causality of this association is controversial. In this study we tested the effect of a hyperhomocysteinemia-inducing diet in the ArcA␤ transgenic AD mouse model. At 14 months of age, the hyperhomocysteinemia-inducing diet yielded higher plasma homocysteine levels in ArcA␤ mice compared with wild-type mice. Levels of plasma 5-methyltetrahydrofolate (5-MTHF) in 14-month-old mice on hyperhomocysteinemiainducing diet were lower in the transgenic than in the wild-type mice. The folate derivate 5-MTHF serves as cofactor in homocysteine metabolism. Oxidative stress, which occurs in the course of disease in the ArcA␤ mice, consumes 5-MTHF. Thus, the transgenic mice may plausibly be more vulnerable to 5-MTHF-depleting effects of hyperhomocysteinemia and more vulnerable to hyperhomocysteinemia-inducing diet. This argues that AD pathology predisposes to hyperhomocysteinemia, i.e., as a facultative consequence of AD. However, we also observed that dietary-induced folate reduction and homocysteine increase was associated with an increase of plasma (young animals) and brain (older animals) amyloid-␤ concentrations. This suggests that the hyperhomocysteinemia-inducing diet worsened pathology in the transgenic mice. In conclusion, this data may argue that folate reduction and hyperhomocysteinemia may contribute to neurodegeneration and may also be triggered by neurodegenerative processes, i.e., represent both a cause and a consequence of neurodegeneration. Such a vicious cycle may be breakable by dietary or supplementation strategies increasing the availability of 5-MTHF. 8 22 23 [1]. Factors like higher age, male gender, renal dys-30 function, genetic variants, high methionine uptake via 1 These authors contributed equally. protein-rich food, and deficiencies of folate, vitamin 31 B12, and vitamin B6 are linked to hyperhomocys-32 teinemia [2]. The nature of the relationship between 33 hyperhomocysteinemia and AD is controversial [3-5]. 34 Homocysteine is a toxic intermediate of methion-35 ine metabolism. It is either irreversibly metabolized 36 by the vitamin B6-dependent transsulfuration pathway 37 or is recycled to methionine by the folate-and vita-38 min B12-dependent remethylation pathway (Fig. 1). 39 Methionine can be activated to S-adenosylmethionine 40 (SAM), which serves as universal methyl-group donor, 41 e.g., for DNA, RNA, and protein methylation reactions. 42 SAM is thereby converted to S-adenosylhomocysteine 43 (SAH), which is further hydrolyzed to homocysteine 44 in a reversible reaction. Although elevated plasma 307 [6] Clarke R, Smith AD, Jobst KA, Refsum H, Sutton L, Ueland 308 PM (1998) Folate, vitamin B12, and serum total homocysteine 309 levels in confirmed Alzheimer disease. Arch Neurol 55, 1449-310 1455. 311 [7] Linnebank M, Popp J, Smulders Y, Smith D, Semm-312 ler A, Farkas M, Kulic L, Cvetanovska G, Blom H, 313 Stoffel-Wagner B, Kolsch H, Weller M, Jessen F (2010) S-314 adenosylmethionine is decreased in the cerebrospinal fluid 315 of patients with Alzheimer's disease. Neurodegener Dis 7, 316 373-378. 317 [8] Kim JM, Kim SW, Shin IS, Yang SJ, Park WY, Kim SJ, Shin 318 HY, Yoon JS (2008) Folate, vitamin b(12), and homocysteine 319 U n c o r r e c t e d A u t h o r P r o o f M. Farkas et al. / Homocysteine and Folate in AD 7 as risk factors for cognitive decline in the elderly. Psychiatry 320 Investig 5, 36-40. 321 [9] McMahon JA, Green TJ, Skeaff CM, Knight RG, Mann 322 JI, Williams SM (2006) A controlled trial of homocysteine 323 lowering and cognitive performance. N Engl J Med 354, 2764-324 2772. 325 [10] Dangour AD, Whitehouse PJ, Rafferty K, Mitchell SA, Smith 326 L, Hawkesworth S, Vellas B (2010) B-vitamins and fatty acids 327 in the prevention and treatment of Alzheimer's disease and 328 dementia: A systematic review. J Alzheimers Dis 22, 205-329