Alzheimer's disease (AD) is an age-associated progressive
neurodegenerative disorder with
dementia, the exact pathogenic mechanisms of which remain unknown. We previously reported that
homocysteic acid (HA) may be one of the pathological
biomarkers in the brain with AD and that the increased levels of HA may induce the accumulation of intraneuronal
amyloid-beta (Abeta)
peptides. In this study, we further investigated the pathological role of HA in a mouse model of AD. Four-month-old prepathological 3xTg-AD mice exhibited higher levels of HA in the hippocampus than did age-matched nontransgenic mice, suggesting that HA accumulation may precede both Abeta and tau pathologies. We then fed 3-month-old 3xTg-AD mice with
vitamin B6-deficient food for 3 weeks to increase the HA levels in the brain. Concomitantly, mice received either saline or anti-HA antibody intraventricularly via a guide
cannula every 3 days during the course of the B6-deficient diet. We found that mice that received anti-HA antibody significantly resisted
cognitive impairment induced by
vitamin B6 deficiency and that AD-related pathological changes in their brains was attenuated compared with the saline-injected control group. A similar
neuroprotective effect was observed in 12-month-old 3xTg-AD mice that received anti-HA antibody
injections while receiving the regular diet. We conclude that increased brain HA triggers memory impairment and that this condition deteriorates with
amyloid and leads to subsequent neurodegeneration in mouse models of AD.