Limits...
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.

Show MeSH

Related in: MedlinePlus

Thiamet-G prevents cognitive decline in the TAPP mice. A, B. Beginning at 30-32 weeks of age 0, 200 or 500 mkd Thiamet-G treated TAPP mice were tested for cognitive performance in the Morris water maze (MWM). Learning curves were recorded during five consecutive days of training. No significant difference was observed between any of the groups in latency to solve the maze (A) and while a significant main effect was noted by the ANOVA for distance travelled, the post-hoc Tukey’s analysis revealed that there were no significant differences between groups. (B). C. During the probe trial, the latency to solve the maze was recorded and the control TAPP mice (0 mkd Thiamet-G) show significant cognitive impairment compared to untreated age-matched wild-type mice. Conversely, 500 mkd resulted in better performance than the 0 mkd Thiamet-G treated TAPP mice while the performance of 200 mkd TAPP mice is indistinguishable from the untreated age-matched wild-type mice. D. No differences were observed in the distance travelled during the probe trial. Error bars represent standard deviation (± S.D) and p-value result from a one-way analysis of variance (ANOVA) For all panels, n =8 for 0 mkd wild-type mice, n =17 for 0 mkd TAPP mice, n =17 for 500 mkd TAPP mice and n =19 for 200 mkd TAPP mice.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Fig1: Thiamet-G prevents cognitive decline in the TAPP mice. A, B. Beginning at 30-32 weeks of age 0, 200 or 500 mkd Thiamet-G treated TAPP mice were tested for cognitive performance in the Morris water maze (MWM). Learning curves were recorded during five consecutive days of training. No significant difference was observed between any of the groups in latency to solve the maze (A) and while a significant main effect was noted by the ANOVA for distance travelled, the post-hoc Tukey’s analysis revealed that there were no significant differences between groups. (B). C. During the probe trial, the latency to solve the maze was recorded and the control TAPP mice (0 mkd Thiamet-G) show significant cognitive impairment compared to untreated age-matched wild-type mice. Conversely, 500 mkd resulted in better performance than the 0 mkd Thiamet-G treated TAPP mice while the performance of 200 mkd TAPP mice is indistinguishable from the untreated age-matched wild-type mice. D. No differences were observed in the distance travelled during the probe trial. Error bars represent standard deviation (± S.D) and p-value result from a one-way analysis of variance (ANOVA) For all panels, n =8 for 0 mkd wild-type mice, n =17 for 0 mkd TAPP mice, n =17 for 500 mkd TAPP mice and n =19 for 200 mkd TAPP mice.

Mentions: To assess whether increased O-GlcNAc can influence amyloid deposition or cognitive impairment in bigenic TAPP mice, we divided 60 double transgenic TAPP mice into three groups (n = 20) receiving either 0, 200, or 500 mkd of Thiamet-G in their drinking water. We have previously shown oral Thiamet-G treatment of mice over a period of months leads to sustained O-GlcNAc increases in the brains of mice [20]. Parental transgenic Tg2576 mice, which harbor only the APPSwe mutation, develop pronounced memory impairment starting at 6 months of age [15, 30] as judged by performance in the Morris water maze (MWM). Therefore to determine whether increased O-GlcNAc can influence disease progression in TAPP mice we started dosing with Thiamet-G at 10-13 weeks of age and continued until 44-47 weeks of age. Effects of OGA inhibition on cognitive impairment were assessed by performing MWM testing on each of the animals in the three groups starting between 28-32 weeks of age. All data acquisition and data entry was performed blinded with the coding being held by non-experimenters. We find that in the acquisition phase, during which animals engage in spatial learning, the latency to solve the maze was not significantly different between the groups as judged by RM-ANOVA (F5,78 = 0.668, p =0.649) (Figure 1A). Differences in the distance traveled within the maze during this learning phase were significantly different (F5,78 = 2.389, p =0.045), though a Tukey’s post-hoc analysis did not reveal any specific differences between groups (Figure 1B). To clarify whether behavioural changes that might be observed in these studies are due to cognition per se and not due to motor differences between groups, we examined the time spent in the outer ring as a measure of anxiety and swim speed during these acquisition trials. The swim speed was significantly different between groups (F5,78 = 2.817, p =0.022), with the Tukey’s post-hoc analysis indicating that the 500 mkd Thiamet-G treated group was faster than the untreated wild-type control group (p =0.042), perhaps because treatment protects against neurodegeneration of motor neurons as previously observed in JNPL3 mice [16]. There was no difference between the groups in the time spent in the outer ring (F5,78 = 0.758, p =0.582) indicating the animals showed no apparent anxiety effects.Figure 1


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 prevents cognitive decline in the TAPP mice. A, B. Beginning at 30-32 weeks of age 0, 200 or 500 mkd Thiamet-G treated TAPP mice were tested for cognitive performance in the Morris water maze (MWM). Learning curves were recorded during five consecutive days of training. No significant difference was observed between any of the groups in latency to solve the maze (A) and while a significant main effect was noted by the ANOVA for distance travelled, the post-hoc Tukey’s analysis revealed that there were no significant differences between groups. (B). C. During the probe trial, the latency to solve the maze was recorded and the control TAPP mice (0 mkd Thiamet-G) show significant cognitive impairment compared to untreated age-matched wild-type mice. Conversely, 500 mkd resulted in better performance than the 0 mkd Thiamet-G treated TAPP mice while the performance of 200 mkd TAPP mice is indistinguishable from the untreated age-matched wild-type mice. D. No differences were observed in the distance travelled during the probe trial. Error bars represent standard deviation (± S.D) and p-value result from a one-way analysis of variance (ANOVA) For all panels, n =8 for 0 mkd wild-type mice, n =17 for 0 mkd TAPP mice, n =17 for 500 mkd TAPP mice and n =19 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

Fig1: Thiamet-G prevents cognitive decline in the TAPP mice. A, B. Beginning at 30-32 weeks of age 0, 200 or 500 mkd Thiamet-G treated TAPP mice were tested for cognitive performance in the Morris water maze (MWM). Learning curves were recorded during five consecutive days of training. No significant difference was observed between any of the groups in latency to solve the maze (A) and while a significant main effect was noted by the ANOVA for distance travelled, the post-hoc Tukey’s analysis revealed that there were no significant differences between groups. (B). C. During the probe trial, the latency to solve the maze was recorded and the control TAPP mice (0 mkd Thiamet-G) show significant cognitive impairment compared to untreated age-matched wild-type mice. Conversely, 500 mkd resulted in better performance than the 0 mkd Thiamet-G treated TAPP mice while the performance of 200 mkd TAPP mice is indistinguishable from the untreated age-matched wild-type mice. D. No differences were observed in the distance travelled during the probe trial. Error bars represent standard deviation (± S.D) and p-value result from a one-way analysis of variance (ANOVA) For all panels, n =8 for 0 mkd wild-type mice, n =17 for 0 mkd TAPP mice, n =17 for 500 mkd TAPP mice and n =19 for 200 mkd TAPP mice.
Mentions: To assess whether increased O-GlcNAc can influence amyloid deposition or cognitive impairment in bigenic TAPP mice, we divided 60 double transgenic TAPP mice into three groups (n = 20) receiving either 0, 200, or 500 mkd of Thiamet-G in their drinking water. We have previously shown oral Thiamet-G treatment of mice over a period of months leads to sustained O-GlcNAc increases in the brains of mice [20]. Parental transgenic Tg2576 mice, which harbor only the APPSwe mutation, develop pronounced memory impairment starting at 6 months of age [15, 30] as judged by performance in the Morris water maze (MWM). Therefore to determine whether increased O-GlcNAc can influence disease progression in TAPP mice we started dosing with Thiamet-G at 10-13 weeks of age and continued until 44-47 weeks of age. Effects of OGA inhibition on cognitive impairment were assessed by performing MWM testing on each of the animals in the three groups starting between 28-32 weeks of age. All data acquisition and data entry was performed blinded with the coding being held by non-experimenters. We find that in the acquisition phase, during which animals engage in spatial learning, the latency to solve the maze was not significantly different between the groups as judged by RM-ANOVA (F5,78 = 0.668, p =0.649) (Figure 1A). Differences in the distance traveled within the maze during this learning phase were significantly different (F5,78 = 2.389, p =0.045), though a Tukey’s post-hoc analysis did not reveal any specific differences between groups (Figure 1B). To clarify whether behavioural changes that might be observed in these studies are due to cognition per se and not due to motor differences between groups, we examined the time spent in the outer ring as a measure of anxiety and swim speed during these acquisition trials. The swim speed was significantly different between groups (F5,78 = 2.817, p =0.022), with the Tukey’s post-hoc analysis indicating that the 500 mkd Thiamet-G treated group was faster than the untreated wild-type control group (p =0.042), perhaps because treatment protects against neurodegeneration of motor neurons as previously observed in JNPL3 mice [16]. There was no difference between the groups in the time spent in the outer ring (F5,78 = 0.758, p =0.582) indicating the animals showed no apparent anxiety effects.Figure 1

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