Treatment of Alzheimer's Disease with Anti-Homocysteic acid Antibody

Homocysteic 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

Treatment of Alzheimer's Disease with Anti-Homocysteic acid Antibody

Homocysteic 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

Treatment of Alzheimer's Disease with Anti-Homocysteic Acid Antibody in 3xTg-AD Male Mice

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

Treatment of Alzheimer's Disease with Anti-Homocysteic Acid Antibody in 3xTg-AD Male Mice

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

Long-Term Memory Test in the Morris Water Maze task.

<p>Non-transgenic mice had an average score of 3 mice each day. Hemizygous transgenic control (hemizygous + B6 deficient) mice had an average score of 3 transgenic control mice each day. Transgenic experimental (hemizygous + B6 deficient + anti-HA antibody) mice had an average score of 3 transgenic experimental mice each day. 3xTg-AD mice were aged 3 months and 3 weeks. Statistically significant difference was observed after 2 trial days between hemizygous + B6 deficient and hemizygous + B6 deficient + antibody (<i>P</i><0.001) and after 3 trial days between hemizygous + B6 deficient and hemizygous + B6 deficient + antibody (<i>P</i><0.05).</p

HA level in 3xTg-AD mice.

<p>Note: A: Vaccine treatment was started at 12 months. Three months later, urine was collected an entire day and HA level was measured. 3xTg-AD male mice were all homozygous. HA level with vaccine treatment decreased with time, indicating that vaccine efficacy became stronger with time.</p><p><b>Note: For reference, HA level in 12-month-old in 3xTg-AD male mice were observed.</b></p><p>Note: B: After Morris water maze test, these mice were sacrificed and their brains were immediately freezed in liquid nitrogen. Next, HA level was measured with the method described in Materials and Method.</p

HA Level in 3xTg-AD mice brain after Ingesting Vitamin B6-Deficient food for 3 weeks.

<p>Control mice: 3xTg-AD mice at 3 months and 3 weeks with normal feeding. Control mice showed good memory performance, but B6-deficient feeding group showed memory impairment. Whole brain was homogenized with physiological saline and HA level was measured, after the memory task, according to the method described in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0008593#s2" target="_blank">Materials and Methods</a>.</p

Homocysteic Acid Level in 3xTg-AD mice brain at 4 months compared with Non-Tg control mice.

<p>HA level in the brain of 3xTg-AD male mice at 4 months was measured by the method described in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0008593#s2" target="_blank">Materials and Methods</a>. Control was non-Tg male mice at 4 months.</p

Hematoxylin-Eosin Staining of Cortical and Hippocampal Neurons in Control and Experimental Groups.

<p>Mice were treated the same as those shown in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0008593#pone-0008593-g003" target="_blank">Fig. 3</a>.</p

The Effect on Memory Performance of HA Vaccine on Normal Feeding of 3xTg-AD Male Mice.

<p>Mice were 12 months old. Memory performance was measured via the Morris water experiment described in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0008593#s2" target="_blank">Materials and Methods</a>. Statistically significant difference was observed on the third, fourth, and fifth trial days (<i>P</i><0.001). 3xTg-AD male mice were all homozygous (n = 15).</p