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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

Aβ40 and Aβ42 levels. ELISA assays for Aβ40 and Aβ42 were used to assess the quantity of each of these species in the 0, 200 or 500 mkd Thiamet-G treated TAPP mice groups. A. 500 mkd was sufficient to reduce the amount of Aβ42 by half while 200 mkd was ineffective. B. 500 mkd Thiamet-G also showed a trend toward less Aβ40 which was not evident in the 200 mkd group. 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 =14 for 0 mkd TAPP mice, N =16 for 500 mkd TAPP mice and N =13 for 200 mkd TAPP mice.
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Fig5: Aβ40 and Aβ42 levels. ELISA assays for Aβ40 and Aβ42 were used to assess the quantity of each of these species in the 0, 200 or 500 mkd Thiamet-G treated TAPP mice groups. A. 500 mkd was sufficient to reduce the amount of Aβ42 by half while 200 mkd was ineffective. B. 500 mkd Thiamet-G also showed a trend toward less Aβ40 which was not evident in the 200 mkd group. 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 =14 for 0 mkd TAPP mice, N =16 for 500 mkd TAPP mice and N =13 for 200 mkd TAPP mice.

Mentions: Previous work has shown that at 7-8 months of age the single transgenic JNPL3 mice generally perform no worse than age matched wild-type control animals in the MWM [34]. For this reason, and the absence of significant effects on tau phosphorylation, we felt that the cognitive effects of OGA inhibition in this TAPP model reflected in the MWM results may stem from effects of Thiamet-G treatment on accumulation of β-amyloid peptides and be reflected in the extent of amyloid plaque formation. To address this possibility we performed a number of experiments in which the experimenter was blinded using coded samples. The first study established whether Thiamet-G had any impact on the quantities of the amyloidogenic forms of β-amyloid 1-40 and 1-42 (Aβ40, Aβ42). Using widely used commercially available ELISA assays for Aβ40 and Aβ42, we determined that administration of 500 mkd Thiamet-G significantly reduced the quantity of Aβ42 while the 200 mkd treatment had no significant effect on this measure (Figure 5). We also observed a trend toward less Aβ40 in the 500 mkd treatment group that was not present in the 200 mkd group (Figure 5). As described above, O-GlcNAc levels in the 200 mkd group are slightly lower than the 500 mkd group and thus may indicate that a sustained increase in O-GlcNAc levels above a certain threshold must be reached in order to influence the levels of Aβ peptides within brain.Figure 5


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)

Aβ40 and Aβ42 levels. ELISA assays for Aβ40 and Aβ42 were used to assess the quantity of each of these species in the 0, 200 or 500 mkd Thiamet-G treated TAPP mice groups. A. 500 mkd was sufficient to reduce the amount of Aβ42 by half while 200 mkd was ineffective. B. 500 mkd Thiamet-G also showed a trend toward less Aβ40 which was not evident in the 200 mkd group. 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 =14 for 0 mkd TAPP mice, N =16 for 500 mkd TAPP mice and N =13 for 200 mkd TAPP mice.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Fig5: Aβ40 and Aβ42 levels. ELISA assays for Aβ40 and Aβ42 were used to assess the quantity of each of these species in the 0, 200 or 500 mkd Thiamet-G treated TAPP mice groups. A. 500 mkd was sufficient to reduce the amount of Aβ42 by half while 200 mkd was ineffective. B. 500 mkd Thiamet-G also showed a trend toward less Aβ40 which was not evident in the 200 mkd group. 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 =14 for 0 mkd TAPP mice, N =16 for 500 mkd TAPP mice and N =13 for 200 mkd TAPP mice.
Mentions: Previous work has shown that at 7-8 months of age the single transgenic JNPL3 mice generally perform no worse than age matched wild-type control animals in the MWM [34]. For this reason, and the absence of significant effects on tau phosphorylation, we felt that the cognitive effects of OGA inhibition in this TAPP model reflected in the MWM results may stem from effects of Thiamet-G treatment on accumulation of β-amyloid peptides and be reflected in the extent of amyloid plaque formation. To address this possibility we performed a number of experiments in which the experimenter was blinded using coded samples. The first study established whether Thiamet-G had any impact on the quantities of the amyloidogenic forms of β-amyloid 1-40 and 1-42 (Aβ40, Aβ42). Using widely used commercially available ELISA assays for Aβ40 and Aβ42, we determined that administration of 500 mkd Thiamet-G significantly reduced the quantity of Aβ42 while the 200 mkd treatment had no significant effect on this measure (Figure 5). We also observed a trend toward less Aβ40 in the 500 mkd treatment group that was not present in the 200 mkd group (Figure 5). As described above, O-GlcNAc levels in the 200 mkd group are slightly lower than the 500 mkd group and thus may indicate that a sustained increase in O-GlcNAc levels above a certain threshold must be reached in order to influence the levels of Aβ peptides within brain.Figure 5

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