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Pharmacological inhibition of O-GlcNAcase (OGA) prevents cognitive decline and amyloid plaque formation in bigenic tau/APP mutant mice.

Yuzwa SA, Shan X, Jones BA, Zhao G, Woodward ML, Li X, Zhu Y, McEachern EJ, Silverman MA, Watson NV, Gong CX, Vocadlo DJ - Mol Neurodegener (2014)

Bottom Line: We treated double transgenic TAPP mice, which express both mutant human tau and amyloid precursor protein (APP), with a highly selective orally bioavailable inhibitor of the enzyme responsible for removing O-GlcNAc (OGA) to increase O-GlcNAc in the brain.We find that increased O-GlcNAc levels block cognitive decline in the TAPP mice and this effect parallels decreased β-amyloid peptide levels and decreased levels of amyloid plaques.The findings provide good support for OGA as a promising therapeutic target to alter disease progression in Alzheimer disease.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Biology and Biochemistry, Simon Fraser University, 8888 University Dr, Burnaby, BC V5A 1S6, Canada. dvocadlo@sfu.ca.

ABSTRACT

Background: Amyloid plaques and neurofibrillary tangles (NFTs) are the defining pathological hallmarks of Alzheimer's disease (AD). Increasing the quantity of the O-linked N-acetylglucosamine (O-GlcNAc) post-translational modification of nuclear and cytoplasmic proteins slows neurodegeneration and blocks the formation of NFTs in a tauopathy mouse model. It remains unknown, however, if O-GlcNAc can influence the formation of amyloid plaques in the presence of tau pathology.

Results: We treated double transgenic TAPP mice, which express both mutant human tau and amyloid precursor protein (APP), with a highly selective orally bioavailable inhibitor of the enzyme responsible for removing O-GlcNAc (OGA) to increase O-GlcNAc in the brain. We find that increased O-GlcNAc levels block cognitive decline in the TAPP mice and this effect parallels decreased β-amyloid peptide levels and decreased levels of amyloid plaques.

Conclusions: This study indicates that increased O-GlcNAc can influence β-amyloid pathology in the presence of tau pathology. The findings provide good support for OGA as a promising therapeutic target to alter disease progression in Alzheimer disease.

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Related in: MedlinePlus

Thiamet-G reduces plaque load in the TAPP mice. A. Representative 6E10 immunohistochemical analysis used to assess amyloid plaque load in both the cortical and hippocampal regions. B. Quantitative assessment of 6E10 IHC analysis reveals that both 200 and 500 mkd Thiamet-G is sufficient to reduce the number of amyloid plaques in the cortex. C. 500 mkd Thiamet-G significantly reduced the number of amyloid plaques in the hippocampus whereas 200 mkd Thiamet-G was ineffective. Error bars represent standard error of the mean (± S.E.M) and p-values result from student’s unpaired two-tailed t-tests. For all panels, N =12 in each group.
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Fig6: Thiamet-G reduces plaque load in the TAPP mice. A. Representative 6E10 immunohistochemical analysis used to assess amyloid plaque load in both the cortical and hippocampal regions. B. Quantitative assessment of 6E10 IHC analysis reveals that both 200 and 500 mkd Thiamet-G is sufficient to reduce the number of amyloid plaques in the cortex. C. 500 mkd Thiamet-G significantly reduced the number of amyloid plaques in the hippocampus whereas 200 mkd Thiamet-G was ineffective. Error bars represent standard error of the mean (± S.E.M) and p-values result from student’s unpaired two-tailed t-tests. For all panels, N =12 in each group.

Mentions: Finally, we evaluated whether the reduced Aβ42 levels correlated with fewer amyloid plaques within these animals. By quantitative analysis, we observed fewer amyloid plaques in both cortical and hippocampal regions of the brain in the 500 mkd Thiamet-G treated group (Figure 6). Interestingly however, in the cortex we found that 200 mkd was sufficient to reduce the number of amyloid plaques to the same level as seen in mice treated with 500 mkd Thiamet-G despite this dose being unable to significantly reduce levels of Aβ42 as assessed by ELISA (Figure 6B). It is interesting to note that O-GlcNAc levels are generally higher in the hippocampus (Figure 2C) than in the cortex, yet we observe larger reductions in the number of plaques in cortex in both dose groups than observed in the hippocampus. Perhaps different brain regions have differing capacities to increase O-GlcNAc levels and this may be coupled to tissue dependent differences in amyloid deposition that depend on O-GlcNAc levels. Further, perhaps differences in the levels of Aβ42 within certain brain regions are also present yet were not detected here because the ELISAs are conducted on homogenates obtained from complete brain hemispheres. Using whole brain homogenates might mask small differences in Aβ42 levels present in certain brain regions. These observations suggest that increased O-GlcNAc could influence both β-amyloid peptide production or clearance as well as assembly/clearance of amyloid plaques arising from Aβ42.Figure 6


Pharmacological inhibition of O-GlcNAcase (OGA) prevents cognitive decline and amyloid plaque formation in bigenic tau/APP mutant mice.

Yuzwa SA, Shan X, Jones BA, Zhao G, Woodward ML, Li X, Zhu Y, McEachern EJ, Silverman MA, Watson NV, Gong CX, Vocadlo DJ - Mol Neurodegener (2014)

Thiamet-G reduces plaque load in the TAPP mice. A. Representative 6E10 immunohistochemical analysis used to assess amyloid plaque load in both the cortical and hippocampal regions. B. Quantitative assessment of 6E10 IHC analysis reveals that both 200 and 500 mkd Thiamet-G is sufficient to reduce the number of amyloid plaques in the cortex. C. 500 mkd Thiamet-G significantly reduced the number of amyloid plaques in the hippocampus whereas 200 mkd Thiamet-G was ineffective. Error bars represent standard error of the mean (± S.E.M) and p-values result from student’s unpaired two-tailed t-tests. For all panels, N =12 in each group.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4232697&req=5

Fig6: Thiamet-G reduces plaque load in the TAPP mice. A. Representative 6E10 immunohistochemical analysis used to assess amyloid plaque load in both the cortical and hippocampal regions. B. Quantitative assessment of 6E10 IHC analysis reveals that both 200 and 500 mkd Thiamet-G is sufficient to reduce the number of amyloid plaques in the cortex. C. 500 mkd Thiamet-G significantly reduced the number of amyloid plaques in the hippocampus whereas 200 mkd Thiamet-G was ineffective. Error bars represent standard error of the mean (± S.E.M) and p-values result from student’s unpaired two-tailed t-tests. For all panels, N =12 in each group.
Mentions: Finally, we evaluated whether the reduced Aβ42 levels correlated with fewer amyloid plaques within these animals. By quantitative analysis, we observed fewer amyloid plaques in both cortical and hippocampal regions of the brain in the 500 mkd Thiamet-G treated group (Figure 6). Interestingly however, in the cortex we found that 200 mkd was sufficient to reduce the number of amyloid plaques to the same level as seen in mice treated with 500 mkd Thiamet-G despite this dose being unable to significantly reduce levels of Aβ42 as assessed by ELISA (Figure 6B). It is interesting to note that O-GlcNAc levels are generally higher in the hippocampus (Figure 2C) than in the cortex, yet we observe larger reductions in the number of plaques in cortex in both dose groups than observed in the hippocampus. Perhaps different brain regions have differing capacities to increase O-GlcNAc levels and this may be coupled to tissue dependent differences in amyloid deposition that depend on O-GlcNAc levels. Further, perhaps differences in the levels of Aβ42 within certain brain regions are also present yet were not detected here because the ELISAs are conducted on homogenates obtained from complete brain hemispheres. Using whole brain homogenates might mask small differences in Aβ42 levels present in certain brain regions. These observations suggest that increased O-GlcNAc could influence both β-amyloid peptide production or clearance as well as assembly/clearance of amyloid plaques arising from Aβ42.Figure 6

Bottom Line: We treated double transgenic TAPP mice, which express both mutant human tau and amyloid precursor protein (APP), with a highly selective orally bioavailable inhibitor of the enzyme responsible for removing O-GlcNAc (OGA) to increase O-GlcNAc in the brain.We find that increased O-GlcNAc levels block cognitive decline in the TAPP mice and this effect parallels decreased β-amyloid peptide levels and decreased levels of amyloid plaques.The findings provide good support for OGA as a promising therapeutic target to alter disease progression in Alzheimer disease.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Biology and Biochemistry, Simon Fraser University, 8888 University Dr, Burnaby, BC V5A 1S6, Canada. dvocadlo@sfu.ca.

ABSTRACT

Background: Amyloid plaques and neurofibrillary tangles (NFTs) are the defining pathological hallmarks of Alzheimer's disease (AD). Increasing the quantity of the O-linked N-acetylglucosamine (O-GlcNAc) post-translational modification of nuclear and cytoplasmic proteins slows neurodegeneration and blocks the formation of NFTs in a tauopathy mouse model. It remains unknown, however, if O-GlcNAc can influence the formation of amyloid plaques in the presence of tau pathology.

Results: We treated double transgenic TAPP mice, which express both mutant human tau and amyloid precursor protein (APP), with a highly selective orally bioavailable inhibitor of the enzyme responsible for removing O-GlcNAc (OGA) to increase O-GlcNAc in the brain. We find that increased O-GlcNAc levels block cognitive decline in the TAPP mice and this effect parallels decreased β-amyloid peptide levels and decreased levels of amyloid plaques.

Conclusions: This study indicates that increased O-GlcNAc can influence β-amyloid pathology in the presence of tau pathology. The findings provide good support for OGA as a promising therapeutic target to alter disease progression in Alzheimer disease.

Show MeSH
Related in: MedlinePlus