Journal of Alzheimer’s Disease 21 (2010) 65–66 65
DOI 10.3233/JAD-2010-100144 IOS Press
Commentary
S-Adenosylhomocysteine: A Better Marker
of the Development of Alzheimer’s Disease
than Homocysteine?
Po-Yuan Chang
a, Shao-Chun Lu
band Chu-Huang Chen
c,d,e,∗aDepartment of Internal Medicine, National Taiwan University Hospital and National Taiwan University College
of Medicine, Taipei, Taiwan
bDepartment of Biochemistry and Molecular Biology, National Taiwan University College of Medicine, Taipei,
Taiwan
cVascular and Medicinal Research, Texas Heart Institute at St. Luke’s Episcopal Hospital, Houston, TX, USA dDepartment of Medicine, Baylor College of Medicine, Houston, TX, USA
eDepartment of Medicine, China Medical University Hospital, Taichung, Taiwan
The article by Popp and colleagues [1] highlights the association between the alteration in homocysteine metabolism and Alzheimer’s disease (AD) patholo-gy (as reflected by the cerebrospinal fluid biomarkers amyloid-β1−42and P-tau181). Moreover, they raise the question as to whetherS-adenosylhomocysteine (SAH) is a better marker of the development of AD than homo-cysteine. Although Popp and colleagues [1] found that phosphorylated tau was strongly associated with SAH rather than homocysteine, they did not study the mech-anism underlying the SAH-AD association. The da-ta from clinical and epidemiologic studies do not con-sistently show that plasma levels of homocysteine are associated with an increased risk of cognitive impair-ment and AD [2–4]. Similarly, clinical trials of vitamin B supplementation as a means of lowering homocys-teine levels to prevent cognitive decline in AD patients have not been consistently successful [5,6]. Because
∗Correspondence to: Chu-Huang Chen, MD, PhD, Vascular and Medicinal Research, Texas Heart Institute, 6770 Bertner Avenue, MC 2-255, Houston, TX 77030, USA. Tel.: +1 832 355 9026; E-mail: cchen@heart.thi.tmc.edu.
increasing evidence indicates that high plasma levels of homocysteine may not be a marker of vascular in-jury [6], the finding by Popp and colleagues that SAH, not homocysteine, is associated with tau accumulation in AD patients is not surprising.
Vascular injury is an essential component underly-ing both AD and cognitive impairment in the elderly. The relationship between hyperhomocysteinemia and vascular disease is somewhat controversial. Increasing data suggest SAH is a better indicator of cardiovascular disease and atherosclerosis than is homocysteine [7,8]. In neurodegenerative diseases, elevated homocysteine levels can lead to higher brain levels of SAH and, in turn, increase phosphorylation of tau [9], supporting the crucial role of SAH in the development of AD. Despite the strong association of increased SAH and tau in AD patients, the molecular mechanisms of SAH-induced neuronal injury (which are most likely vascular) are not clear [7,8]. We have recently studied the mechanisms involved in vascular damage induced by homocysteine and SAH [10].
In our study, exposure of human coronary artery en-dothelial cells to homocysteine alone, even at
66 P.-Y. Chang et al. / S-Adenosylhomocysteine: A Better Marker of the Development of Alzheimer’s Disease than Homocysteine?
physiologic concentrations (500µmol/L), did not affect cell integrity, including cell survival, cell cycle transi-tion, and growth factor expression. However, low con-centrations (25µmol/L) of homocysteine induced cyto-toxic changes in endothelial cells under culture condi-tions that increased the intracellular level of SAH [10]. We believe that in the absence of SAH, the vascular ef-fects of homocysteine are negligible, even at the supra-physiologic concentrations used in many in vitro stud-ies.
The critical role of SAH, rather than homocysteine, in inducing damage in vascular endothelial cells may help explain the lack of health benefits observed in sev-eral nutritional intervention trials [5], in which vitamin supplementation decreased plasma levels of homocys-teine but not SAH. Unlike homocyshomocys-teine, SAH levels in the plasma are not related to vitamin B6, vitamin B12, or folic acid concentrations [11,12]. Therefore, the SAH-vascular injury-AD axis may be considered one of several mechanisms linking homocysteine metabolism to the development of AD pathology [13–15]. Given the increasing evidence of the detrimental vascular ef-fects of SAH, it would be of considerable interest to see a large-scale, prospective study of the relationship between plasma or cerebrospinal fluid levels of SAH and the development of AD.
ACKNOWLEDGMENTS
The authors thank Rebecca Bartow, Ph.D., of the Texas Heart Institute at St. Luke’s Episcopal Hospi-tal for editorial assistance, and Miss Yi-Jie Chen for technical assistance.
Supported in part by research grant 1-04-RA-13 from the American Diabetes Association; grants NSC 91-2320-B-002-185, 93-2314-B-002-125, 94-2320-B-002-121, 95-2320-B-002-116, 98-2628-B-002-088 from the National Science Council, Taiwan; grants NTUH92A14, 93A02, 95S342, 96S643 from National Taiwan University Hospital, Taiwan.
Authors’ disclosures available online (http://www.j-alz.com/disclosures/view.php?id=360).
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