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Cognition, learning behaviour and hippocampal synaptic plasticity are not disrupted in mice over-expressing the cholesterol transporter ABCG1.

Parkinson PF, Kannangara TS, Eadie BD, Burgess BL, Wellington CL, Christie BR - Lipids Health Dis (2009)

Bottom Line: Extra copies of the genes on chromosome 21 may also play an important role in the accelerated onset of AD in DS individuals.Growing evidence suggests an important function for cholesterol in the pathogenesis of AD, particularly in APP metabolism and production of A beta peptides.The ATP-Binding Cassette-G1 (ABCG1) transporter is located on chromosome 21, and participates in the maintenance of tissue cholesterol homeostasis.

View Article: PubMed Central - HTML - PubMed

Affiliation: The Department of Pathology and Laboratory Medicine, Child and Family Research Institute, University of British Columbia, Vancouver, BC, Canada. parkinsonpam@gmail.com

ABSTRACT

Background: Cognitive deficits are a hallmark feature of both Down Syndrome (DS) and Alzheimer's Disease (AD). Extra copies of the genes on chromosome 21 may also play an important role in the accelerated onset of AD in DS individuals. Growing evidence suggests an important function for cholesterol in the pathogenesis of AD, particularly in APP metabolism and production of A beta peptides. The ATP-Binding Cassette-G1 (ABCG1) transporter is located on chromosome 21, and participates in the maintenance of tissue cholesterol homeostasis.

Results: To assess the role of ABCG1 in DS-related cognition, we evaluated the cognitive performance of mice selectively over-expressing the ABCG1 gene from its endogenous regulatory signals. Both wild-type and ABCG1 transgenic mice performed equivalently on several behavioral tests, including measures of anxiety, as well as on reference and working memory tasks. No deficits in hippocampal CA1 synaptic plasticity as determined with electrophysiological studies were apparent in mice over-expressing ABCG1.

Conclusion: These findings indicate that although ABCG1 may play a role in maintaining cellular or tissue cholesterol homeostasis, it is unlikely that excess ABCG1 expression contributes to the cognitive deficits in DS individuals.

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Related in: MedlinePlus

ABCG1 BAC Tg mice over-express the ABCG1 transporter in the cortex, hippocampus, and cerebellum, and show normal behaviour. A) Crude membrane fractions were extracted from dissected brain regions and were subjected to Western blot. Blots were probed by polyclonal antibodies recognizing human and murine ABCG1 or Na/K-ATPase as a loading control. ABCG1 protein levels are increased 6-fold in cortex (Cor) and hippocampus (Hipp) and 3-fold in cerebellum (Cer) of ABCG1-BAC-Tg (Tg) mice relative to baseline levels in the equivalent region from wild-type (WT) controls. B) SHRPA primary screen on ABCG1 BAC Tg (ABCG1; n = 11) and wild-type (WT; n = 11) mice. Primary screen involves physiological profiling of each mouse, using a number of test categories and assigning a rating for each mouse in each category. All p values are non-significant when compared to WT animals.
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Figure 1: ABCG1 BAC Tg mice over-express the ABCG1 transporter in the cortex, hippocampus, and cerebellum, and show normal behaviour. A) Crude membrane fractions were extracted from dissected brain regions and were subjected to Western blot. Blots were probed by polyclonal antibodies recognizing human and murine ABCG1 or Na/K-ATPase as a loading control. ABCG1 protein levels are increased 6-fold in cortex (Cor) and hippocampus (Hipp) and 3-fold in cerebellum (Cer) of ABCG1-BAC-Tg (Tg) mice relative to baseline levels in the equivalent region from wild-type (WT) controls. B) SHRPA primary screen on ABCG1 BAC Tg (ABCG1; n = 11) and wild-type (WT; n = 11) mice. Primary screen involves physiological profiling of each mouse, using a number of test categories and assigning a rating for each mouse in each category. All p values are non-significant when compared to WT animals.

Mentions: As previously reported [6], over-expression of ABCG1 was observed in the brains of ABCG1 transgenic mice that were generated using a BAC insertion of the full human ABCG1 gene (ABCG1 BAC Tg mice), with protein levels between 3–8 fold higher than that observed in wild-type littermate control animals (Figure 1A). The level of over-expression varied with brain region, with greater over-expression in the cortex and hippocampus as compared to the cerebellum. This verified that our transgene does in fact significantly increase ABCG1 protein levels in the brain over endogenous levels.


Cognition, learning behaviour and hippocampal synaptic plasticity are not disrupted in mice over-expressing the cholesterol transporter ABCG1.

Parkinson PF, Kannangara TS, Eadie BD, Burgess BL, Wellington CL, Christie BR - Lipids Health Dis (2009)

ABCG1 BAC Tg mice over-express the ABCG1 transporter in the cortex, hippocampus, and cerebellum, and show normal behaviour. A) Crude membrane fractions were extracted from dissected brain regions and were subjected to Western blot. Blots were probed by polyclonal antibodies recognizing human and murine ABCG1 or Na/K-ATPase as a loading control. ABCG1 protein levels are increased 6-fold in cortex (Cor) and hippocampus (Hipp) and 3-fold in cerebellum (Cer) of ABCG1-BAC-Tg (Tg) mice relative to baseline levels in the equivalent region from wild-type (WT) controls. B) SHRPA primary screen on ABCG1 BAC Tg (ABCG1; n = 11) and wild-type (WT; n = 11) mice. Primary screen involves physiological profiling of each mouse, using a number of test categories and assigning a rating for each mouse in each category. All p values are non-significant when compared to WT animals.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2654451&req=5

Figure 1: ABCG1 BAC Tg mice over-express the ABCG1 transporter in the cortex, hippocampus, and cerebellum, and show normal behaviour. A) Crude membrane fractions were extracted from dissected brain regions and were subjected to Western blot. Blots were probed by polyclonal antibodies recognizing human and murine ABCG1 or Na/K-ATPase as a loading control. ABCG1 protein levels are increased 6-fold in cortex (Cor) and hippocampus (Hipp) and 3-fold in cerebellum (Cer) of ABCG1-BAC-Tg (Tg) mice relative to baseline levels in the equivalent region from wild-type (WT) controls. B) SHRPA primary screen on ABCG1 BAC Tg (ABCG1; n = 11) and wild-type (WT; n = 11) mice. Primary screen involves physiological profiling of each mouse, using a number of test categories and assigning a rating for each mouse in each category. All p values are non-significant when compared to WT animals.
Mentions: As previously reported [6], over-expression of ABCG1 was observed in the brains of ABCG1 transgenic mice that were generated using a BAC insertion of the full human ABCG1 gene (ABCG1 BAC Tg mice), with protein levels between 3–8 fold higher than that observed in wild-type littermate control animals (Figure 1A). The level of over-expression varied with brain region, with greater over-expression in the cortex and hippocampus as compared to the cerebellum. This verified that our transgene does in fact significantly increase ABCG1 protein levels in the brain over endogenous levels.

Bottom Line: Extra copies of the genes on chromosome 21 may also play an important role in the accelerated onset of AD in DS individuals.Growing evidence suggests an important function for cholesterol in the pathogenesis of AD, particularly in APP metabolism and production of A beta peptides.The ATP-Binding Cassette-G1 (ABCG1) transporter is located on chromosome 21, and participates in the maintenance of tissue cholesterol homeostasis.

View Article: PubMed Central - HTML - PubMed

Affiliation: The Department of Pathology and Laboratory Medicine, Child and Family Research Institute, University of British Columbia, Vancouver, BC, Canada. parkinsonpam@gmail.com

ABSTRACT

Background: Cognitive deficits are a hallmark feature of both Down Syndrome (DS) and Alzheimer's Disease (AD). Extra copies of the genes on chromosome 21 may also play an important role in the accelerated onset of AD in DS individuals. Growing evidence suggests an important function for cholesterol in the pathogenesis of AD, particularly in APP metabolism and production of A beta peptides. The ATP-Binding Cassette-G1 (ABCG1) transporter is located on chromosome 21, and participates in the maintenance of tissue cholesterol homeostasis.

Results: To assess the role of ABCG1 in DS-related cognition, we evaluated the cognitive performance of mice selectively over-expressing the ABCG1 gene from its endogenous regulatory signals. Both wild-type and ABCG1 transgenic mice performed equivalently on several behavioral tests, including measures of anxiety, as well as on reference and working memory tasks. No deficits in hippocampal CA1 synaptic plasticity as determined with electrophysiological studies were apparent in mice over-expressing ABCG1.

Conclusion: These findings indicate that although ABCG1 may play a role in maintaining cellular or tissue cholesterol homeostasis, it is unlikely that excess ABCG1 expression contributes to the cognitive deficits in DS individuals.

Show MeSH
Related in: MedlinePlus