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Abstract
AbstractHomocysteic acid (HA) may play an important role in Alzhiemer disease (AD) as we previously reported that HA induced accumulation of intraneuronal A[beta]42. In this study, we first analyzed HA levels in a mouse model of AD. 4-month old pre-pathologic 3xTg-AD mice exhibited higher levels of HA in the hippocampus as compared to age-matched nontransgenic, suggesting that HA accumulation may precede both A[beta] and tau pathologies. To further determine the pathogenic role of HA in AD, we treated young 3xTg-AD mice with vitamin B6-deficient food for 3 weeks to induce the production of HA in the brain. Concominantly, mice received either saline or anti-HA antibody intraventricularly using a guide cannula every 3 days. Mice received anti-HA antibody significantly rescued cognitive impairment induced by vitamin B6 deficiency. Pathologically, 3-week treatment with vitamin B-6 deficient food resulted in strong neurodegeneration in the hippocampal CA1 zone and decreased hippocampal volume. In contrast, anti-HA antibody treatment attenuated these pathological changes. Taken together, we conclude that increased brain HA triggers memory impairment whose condition was deteriorated by amyloid and subsequent neurodegeneration and reduction of neurogenesis. Our results indicate a pathogenic role of HA in AD.
Highlights
Amyloid plaques and neurofibrillary tangles are the two pathophysiological hallmarks of Alzheimer’s disease (AD)
Tg control fed normal food: normal, good memory (C) Tg experiment: normal, good memory (D) Tg: Transgenic Figure A and B illustrate that vitamin B6-deficient food induced an anxiety reaction and D illustrates that homocysteic acid (HA) did the same
It can be inferred that transgenic control mice themselves functioned normally, as on being fed normal food they displayed normal memory performance
Summary
Amyloid plaques and neurofibrillary tangles are the two pathophysiological hallmarks of Alzheimer’s disease (AD). The 3xTg-AD mice develop extracellular Aß deposits prior to tangle formation, consistent with the amyloid cascade hypothesis. Despite equivalent overexpression of the human ßAPP and human tau transgenes, Aß deposition develops prior to the tangle pathology, consistent with the amyloid cascade hypothesis These mice exhibit deficits in synaptic plasticity, including long-term potentiation (LTP) that occurs prior to extracellular Aß deposition and tau pathology, but is associated with intracellular Aß immunoreactivity. These studies support the view that synaptic dysfunction is a proximal defect in the pathobiology of AD, preceding extracellular plaque formation and neurofibrillary pathology. Homocysteic acid was added to the culture medium and incubation was performed for 48 h
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