Year-end Sale % OFF 
Abstract
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 (Aβ) 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 Aβ 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.
Highlights
Amyloid plaques and neurofibrillary tangles are the two pathophysiological hallmarks of Alzheimer’s disease (AD)
Since we observed a preventive effect of anti-homocysteic acid (HA) antibody in the acceleration of the pathogenesis of AD in 3xTg-AD mice induced by vitamin B6-deficient food, we looked for a curative effect of anti-HA antibody on the established pathological changes in 3xTg-AD mice with AD. 3xTg-AD hemizygous 7-month-old male mice were fed vitamin B6-deficient food for 3 weeks and anti-HA antibody
B6-deficient food induces an increase in homocysteine, homocysteine sulfinic acid, and HA levels [10]
Summary
Amyloid plaques and neurofibrillary tangles are the two pathophysiological hallmarks of Alzheimer’s disease (AD). Intracellular amyloid-beta 42 (Ab42) is increasingly being recognized as an early pathological trigger that can lead to amyloid plaques and may even induce neurofibrillary tangles. We previously reported that homocysteic acid (HA) induces intracellular accumulation of Ab42 and that the production of a-synuclein in the presence of methionine results in cell death [1,19]. The 3xTg-AD mouse model showed memory impairment at an early age because of Ab accumulation in neuronal cells [8,9]. The brain HA production in the 3xTgAD mice was increased by feeding them with a vitamin B6deficient diet for 3 weeks. These pathological changes as well as cognitive impairments were significantly mitigated by concomitant intracranial injections of anti-HA antibody in these mice. Our findings suggest that increased HA may partly contribute to the progression of AD in the mouse model
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
