Impaired spatial memory in APP-overexpressing mice on a homocysteinemia-inducing diet

Neurobiol Aging. 2007 Aug;28(8):1195-205. doi: 10.1016/j.neurobiolaging.2006.05.035. Epub 2006 Jul 11.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Amyloid beta-Protein Precursor / genetics*
  • Amyloid beta-Protein Precursor / metabolism
  • Analysis of Variance
  • Animals
  • Behavior, Animal / physiology
  • Female
  • Homocystine / administration & dosage
  • Homocystine / adverse effects
  • Homocystine / blood
  • Hyperhomocysteinemia / complications*
  • Hyperhomocysteinemia / etiology
  • Maze Learning / physiology
  • Memory Disorders / etiology*
  • Mice
  • Mice, Transgenic
  • Neuropsychological Tests
  • Pteroylpolyglutamic Acids / metabolism
  • Space Perception / physiology*


  • Amyloid beta-Protein Precursor
  • Pteroylpolyglutamic Acids
  • Homocystine