The S-adenosyl homocysteine hydrolase inhibitor 3-deaza-adenosine prevents oxidative damage and cognitive impairment following folate and vitamin E deprivation in a murine model of age-related, oxidative stress-induced neurodegeneration.
Deficiencies in folate promote neurodegeneration and potentiate the influence of other risk factors for neurodegeneration. This is accomplished at least in part by increasing levels of the neurotoxin homocysteine (HC). The S-adenosyl homocysteine (SAH) hydrolase inhibitor 3-deaza-adenosine (DZA) prevents HC accumulation following folate deprivation. We tested the ability of dietary supplementation with DZA to counteract the deleterious influence of folate deprivation. Folate deficiency has previously been shown to potentiate the impact of apolipoprotein E (ApoE); ApoE-/- mice deprived of folate demonstrated increased oxidative damage in brain tissue and impaired cognitive performance as compared to normal mice or to ApoE-/- mice receiving folate. Herein, we demonstrate that dietary supplementation with DZA prevented both the increase in oxidative damage and impaired cognition characteristic of ApoE-/- mice following folate deprivation. These findings suggest that manipulation of the methionine cycle by DZA can counteract folate deficiency. Because folate deprivation, increased HC, and apolipoprotein E deficiency are all risk factors for Alzheimer's disease, these findings also underscore that DZA might be useful in a therapeutic approach to delay neurodegeneration in Alzheimer's disease.
Shea
Thomas B
TB
Center for Cellular Neurobiology and Neurodegeneration Research, Department of Biological Sciences, University of Massachusetts-Lowell, Lowell, MA, USA. Thomas_Shea@uml.edu
Ashline
David
D
Ortiz
Daniela
D
Milhalik
Shelia
S
Rogers
Eugene
E
D043383:Adenosylhomocysteinase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D001921:Brain / Q000187:drug effects / Q000201:enzymology; D001923:Brain Chemistry / Q000187:drug effects / Q000502:physiology; D003072:Cognition Disorders / Q000188:drug therapy* / Q000201:enzymology / Q000503:physiopathology; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005494:Folic Acid Deficiency / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology; D006710:Homocysteine / Q000378:metabolism; D008297:Male; D008715:Methionine / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D019636:Neurodegenerative Diseases / Q000188:drug therapy* / Q000201:enzymology / Q000503:physiopathology; D018696:Neuroprotective Agents / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects* / Q000502:physiology; D014372:Tubercidin / Q000494:pharmacology*; D014811:Vitamin E Deficiency / Q000150:complications / Q000188:drug therapy / Q000503:physiopathology
D001057:Apolipoproteins E; D004791:Enzyme Inhibitors; D018696:Neuroprotective Agents; C018258:3-deazaadenosine; D006710:Homocysteine; D008715:Methionine; D043383:Adenosylhomocysteinase; D014372:Tubercidin