Impaired spatial memory in APP-overexpressing mice on a homocysteinemia-inducing diet.
Consumption of a diet that significantly elevates homocysteine (homocysteinemia) induces cell death in the CA3 hippocampal subfield in amyloid precursor protein (APP) over-expressing transgenic mice but not in wild-type controls. We assessed behavioral and other neuropathological effects of a homocysteinemia-inducing diet in aged APP-overexpressing mice. Starting at 16-18 months of age, mice were fed either a treatment diet lacking folate, choline, and methionine, and supplemented with homocysteine, or a control diet containing normal amounts of folate, choline and methionine but no homocysteine. After 5 months on the experimental diets, performance on a delayed non-matching-to-position working-memory task was unimpaired. In contrast, spatial reference memory in the water maze was impaired in transgenic mice on the treatment diet. Transgenic mice had higher homocysteine levels than wild-type mice even when fed the control diet, suggesting an effect of genotype on homocysteine metabolism. Methyl-donor deficiency did not alter amyloid deposition in the transgenic mice. These results suggest that disrupted homocysteine metabolism may induce Abeta-associated memory impairments and neurodegeneration in APP overexpressing mice.
Bernardo
Alexandra
A
Department of Pharmacology, Vanderbilt University, Nashville, TN 37232-0325, United States.
McCord
Meghan
M
Troen
Aron M
AM
Allison
John D
JD
McDonald
Michael P
MP
D016564:Amyloid beta-Protein Precursor / Q000235:genetics* / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D005260:Female; D006711:Homocystine / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood; D020138:Hyperhomocysteinemia / Q000150:complications* / Q000209:etiology; D018782:Maze Learning / Q000502:physiology; D008569:Memory Disorders / Q000209:etiology*; D051379:Mice; D008822:Mice, Transgenic; D009483:Neuropsychological Tests; D011624:Pteroylpolyglutamic Acids / Q000378:metabolism; D013028:Space Perception / Q000502:physiology*
D016564:Amyloid beta-Protein Precursor; D011624:Pteroylpolyglutamic Acids; D006711:Homocystine