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Impaired structural correlates of memory in Alzheimer's disease mice.

Badhwar A, Lerch JP, Hamel E, Sled JG - Neuroimage Clin (2013)

Bottom Line: The healthy adult brain demonstrates robust learning-induced neuroanatomical plasticity.Using high-resolution post-mortem MRI and deformation-based morphometry, we demonstrate spatial learning and memory-induced focal volume increase in the hippocampus of wild-type mice, an effect that was severely attenuated in APP mice, consistent with their unsuccessful performance in the spatial Morris water maze.Pioglitazone-treatment in APP mice completely rescued functional hyperemia and exerted beneficial effects on spatial learning and memory-recall, but it did not improve hippocampal plasticity.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Cerebrovascular Research, Montreal Neurological Institute, McGill University, Montréal, QC H3A 2B4, Canada.

ABSTRACT
The healthy adult brain demonstrates robust learning-induced neuroanatomical plasticity. While altered neuroanatomical plasticity is suspected to be a factor mitigating the progressive cognitive decline in Alzheimer's disease (AD), it is not known to what extent this plasticity is affected by AD. We evaluated whether spatial learning and memory-induced neuroanatomical plasticity are diminished in an adult mouse model of AD (APP mice) featuring amyloid beta-driven cognitive and cerebrovascular dysfunction. We also evaluated the effect of early, long-term pioglitazone-treatment on functional hyperemia, spatial learning and memory, and associated neuroanatomical plasticity. Using high-resolution post-mortem MRI and deformation-based morphometry, we demonstrate spatial learning and memory-induced focal volume increase in the hippocampus of wild-type mice, an effect that was severely attenuated in APP mice, consistent with their unsuccessful performance in the spatial Morris water maze. These findings implicate impaired neuroanatomical plasticity as an important contributing factor to cognitive deficits in the APP mouse model of AD. Pioglitazone-treatment in APP mice completely rescued functional hyperemia and exerted beneficial effects on spatial learning and memory-recall, but it did not improve hippocampal plasticity.

No MeSH data available.


Related in: MedlinePlus

Activity-induced CBF deficits in APP mice are normalized by pioglitazone. CBF changes were measured in the somatosensory cortex before and during whisker stimulation using laser Doppler flowmetry in 3-month and 6-month-old mice. Activity-induced CBF increase in 3-month-old APP mice (, n = 5) was reduced compared to WT mice (, n = 8), shown using (A) average LDF tracings for the entire 20 second stimulation period, and (B) overall means of the maximal percent change of CBF from baseline. Statistical analysis used was an unpaired two-tailed t-test (Bonferroni corrected). After 3 days of pioglitazone-treatment, the evoked CBF response measured in the same APP mice () was normalized completely, and remained unchanged in the WT mice (). Statistical analysis used was a paired two-tailed t-test. (C) Compared to untreated WT mice (, n = 5), the deficit in the activity-induced CBF response was present in 6-month-old untreated APP mice (, n = 5). The activity-induced CBF response in 6-month-old APP mice (, n = 4) treated for 3 months with pioglitazone did not differ from untreated and treated WT mice (, n = 5), as shown using a two-way ANOVA. p < 0.05, p < 0.01, p < 0.001. Shaded area on line tracings in (A) define the SEM at each point. Error bars: SEM, CBF: cerebral blood flow, pio: pioglitazone, WT: wild-type.
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f0005: Activity-induced CBF deficits in APP mice are normalized by pioglitazone. CBF changes were measured in the somatosensory cortex before and during whisker stimulation using laser Doppler flowmetry in 3-month and 6-month-old mice. Activity-induced CBF increase in 3-month-old APP mice (, n = 5) was reduced compared to WT mice (, n = 8), shown using (A) average LDF tracings for the entire 20 second stimulation period, and (B) overall means of the maximal percent change of CBF from baseline. Statistical analysis used was an unpaired two-tailed t-test (Bonferroni corrected). After 3 days of pioglitazone-treatment, the evoked CBF response measured in the same APP mice () was normalized completely, and remained unchanged in the WT mice (). Statistical analysis used was a paired two-tailed t-test. (C) Compared to untreated WT mice (, n = 5), the deficit in the activity-induced CBF response was present in 6-month-old untreated APP mice (, n = 5). The activity-induced CBF response in 6-month-old APP mice (, n = 4) treated for 3 months with pioglitazone did not differ from untreated and treated WT mice (, n = 5), as shown using a two-way ANOVA. p < 0.05, p < 0.01, p < 0.001. Shaded area on line tracings in (A) define the SEM at each point. Error bars: SEM, CBF: cerebral blood flow, pio: pioglitazone, WT: wild-type.

Mentions: Neural activity-evoked CBF response provides an index of neurovascular coupling. The CBF response evoked by whisker stimulation in the somatosensory cortex was significantly decreased in young APP mice, as compared to WT littermates (21.2 ± 0.4% vs 29.3 ± 0.9%, p < 0.05) (Fig. 1A,B), and persisted with age (17.7 ± 1.8% vs 26.8 ± 1.8%, p < 0.01) (Fig. 1C). Average percent flow deficit measured in APP mice was 27.8% at 3-months of age, and 34.2% at 6-months of age (Fig. 1B,C). Pioglitazone-treatment fully normalized this response with as little as 3-days of treatment (Fig. 1B), an effect that was maintained with long-term treatment (Fig. 1C). A small, but non-significant, enhancing effect on the average percent flow increase was observed in WT-treated mice (Fig. 1C).


Impaired structural correlates of memory in Alzheimer's disease mice.

Badhwar A, Lerch JP, Hamel E, Sled JG - Neuroimage Clin (2013)

Activity-induced CBF deficits in APP mice are normalized by pioglitazone. CBF changes were measured in the somatosensory cortex before and during whisker stimulation using laser Doppler flowmetry in 3-month and 6-month-old mice. Activity-induced CBF increase in 3-month-old APP mice (, n = 5) was reduced compared to WT mice (, n = 8), shown using (A) average LDF tracings for the entire 20 second stimulation period, and (B) overall means of the maximal percent change of CBF from baseline. Statistical analysis used was an unpaired two-tailed t-test (Bonferroni corrected). After 3 days of pioglitazone-treatment, the evoked CBF response measured in the same APP mice () was normalized completely, and remained unchanged in the WT mice (). Statistical analysis used was a paired two-tailed t-test. (C) Compared to untreated WT mice (, n = 5), the deficit in the activity-induced CBF response was present in 6-month-old untreated APP mice (, n = 5). The activity-induced CBF response in 6-month-old APP mice (, n = 4) treated for 3 months with pioglitazone did not differ from untreated and treated WT mice (, n = 5), as shown using a two-way ANOVA. p < 0.05, p < 0.01, p < 0.001. Shaded area on line tracings in (A) define the SEM at each point. Error bars: SEM, CBF: cerebral blood flow, pio: pioglitazone, WT: wild-type.
© Copyright Policy - open-access
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3814975&req=5

f0005: Activity-induced CBF deficits in APP mice are normalized by pioglitazone. CBF changes were measured in the somatosensory cortex before and during whisker stimulation using laser Doppler flowmetry in 3-month and 6-month-old mice. Activity-induced CBF increase in 3-month-old APP mice (, n = 5) was reduced compared to WT mice (, n = 8), shown using (A) average LDF tracings for the entire 20 second stimulation period, and (B) overall means of the maximal percent change of CBF from baseline. Statistical analysis used was an unpaired two-tailed t-test (Bonferroni corrected). After 3 days of pioglitazone-treatment, the evoked CBF response measured in the same APP mice () was normalized completely, and remained unchanged in the WT mice (). Statistical analysis used was a paired two-tailed t-test. (C) Compared to untreated WT mice (, n = 5), the deficit in the activity-induced CBF response was present in 6-month-old untreated APP mice (, n = 5). The activity-induced CBF response in 6-month-old APP mice (, n = 4) treated for 3 months with pioglitazone did not differ from untreated and treated WT mice (, n = 5), as shown using a two-way ANOVA. p < 0.05, p < 0.01, p < 0.001. Shaded area on line tracings in (A) define the SEM at each point. Error bars: SEM, CBF: cerebral blood flow, pio: pioglitazone, WT: wild-type.
Mentions: Neural activity-evoked CBF response provides an index of neurovascular coupling. The CBF response evoked by whisker stimulation in the somatosensory cortex was significantly decreased in young APP mice, as compared to WT littermates (21.2 ± 0.4% vs 29.3 ± 0.9%, p < 0.05) (Fig. 1A,B), and persisted with age (17.7 ± 1.8% vs 26.8 ± 1.8%, p < 0.01) (Fig. 1C). Average percent flow deficit measured in APP mice was 27.8% at 3-months of age, and 34.2% at 6-months of age (Fig. 1B,C). Pioglitazone-treatment fully normalized this response with as little as 3-days of treatment (Fig. 1B), an effect that was maintained with long-term treatment (Fig. 1C). A small, but non-significant, enhancing effect on the average percent flow increase was observed in WT-treated mice (Fig. 1C).

Bottom Line: The healthy adult brain demonstrates robust learning-induced neuroanatomical plasticity.Using high-resolution post-mortem MRI and deformation-based morphometry, we demonstrate spatial learning and memory-induced focal volume increase in the hippocampus of wild-type mice, an effect that was severely attenuated in APP mice, consistent with their unsuccessful performance in the spatial Morris water maze.Pioglitazone-treatment in APP mice completely rescued functional hyperemia and exerted beneficial effects on spatial learning and memory-recall, but it did not improve hippocampal plasticity.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Cerebrovascular Research, Montreal Neurological Institute, McGill University, Montréal, QC H3A 2B4, Canada.

ABSTRACT
The healthy adult brain demonstrates robust learning-induced neuroanatomical plasticity. While altered neuroanatomical plasticity is suspected to be a factor mitigating the progressive cognitive decline in Alzheimer's disease (AD), it is not known to what extent this plasticity is affected by AD. We evaluated whether spatial learning and memory-induced neuroanatomical plasticity are diminished in an adult mouse model of AD (APP mice) featuring amyloid beta-driven cognitive and cerebrovascular dysfunction. We also evaluated the effect of early, long-term pioglitazone-treatment on functional hyperemia, spatial learning and memory, and associated neuroanatomical plasticity. Using high-resolution post-mortem MRI and deformation-based morphometry, we demonstrate spatial learning and memory-induced focal volume increase in the hippocampus of wild-type mice, an effect that was severely attenuated in APP mice, consistent with their unsuccessful performance in the spatial Morris water maze. These findings implicate impaired neuroanatomical plasticity as an important contributing factor to cognitive deficits in the APP mouse model of AD. Pioglitazone-treatment in APP mice completely rescued functional hyperemia and exerted beneficial effects on spatial learning and memory-recall, but it did not improve hippocampal plasticity.

No MeSH data available.


Related in: MedlinePlus