Reduction of the cerebrovascular volume in a transgenic mouse model of Alzheimer's disease

Bourasset, Fanchon; Ouellet, Mélissa; Tremblay, Cyntia; Julien, Carl; Minh, Tuan Nguyen; Oddo, Salvatore; LaFerla, Frank M.; Calon, Frédéric

doi:10.1016/j.neuropharm.2009.01.006

Cited by 94 publications

(78 citation statements)

References 40 publications

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“…We observed thinner basement membranes in 12-month-old APOE4 mice compared with APOE2 (−29.6%, P o0.01) and APOE3 (−35.1%, P o 0.001), respectively, which may lead to molecule that is used as a vascular space marker as it does not cross the BBB. 13,22 Importantly, V vasc values remain comparable between the three groups of APOE-targeted replacement mice at 2, 4, and 12 months (Figures 4A-4C). This suggests that reduction in relative vessel density may be compensated by an increase in the diameter of blood capillaries or increased paracellular diffusion of sucrose through the BBB, resulting in unchanged apparent V vasc in 12-month-old APOE4 mice.…”

Section: Reduction Of Relative Vessel Density and Thinner Basementmentioning

confidence: 84%

“…4 Since diazepam enters the brain by passive diffusion requiring neither a transporter nor energy, the measured brain uptake of [ 3 H]-diazepam depends on two factors: (1) infusion rate and (2) surface permeability. 13,14,25 Indeed, lipophilic solutes cross the BBB through a transcellular pathway, a process referred to as flow-limited transport. 9,14,28 However, a unique advantage of the in situ brain perfusion technique is to allow complete control on not only the perfusate content and perfusion time, but also the flow rate, by adjusting the pump.…”

Section: Discussionmentioning

confidence: 99%

“…8 Since 100% of the perfused [ 3 H]-diazepam has direct access to the BBB, in accordance with Fick's first law of diffusion, a decrease in [ 3 H]-diazepam uptake can only be explained by a reduced surface permeability of the BBB. 13,22 Finally, considerable changes in BBB integrity have been ruled out by experiments conducted with perfused [ 14 C]-sucrose, systemically injected hIgG and two tight junctions proteins (occludin and claudin-5). Therefore, a decrease in the total BBB surface area accessible to the perfused [ 3 H]-diazepam in the brain remains the most likely explanation for the observed uptake decrease in APOE4 mice.…”

Section: Discussionmentioning

confidence: 99%

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Human Apolipoprotein E ε4 Expression Impairs Cerebral Vascularization and Blood—Brain Barrier Function in Mice

Alata

Yue

St‐Amour

et al. 2014

J Cereb Blood Flow Metab

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104

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Human apolipoprotein E (APOE) exists in three isoforms ε2, ε3, and ε4, of which APOE4 is the main genetic risk factor of Alzheimer's disease (AD). As cerebrovascular defects are associated with AD, we tested whether APOE genotype has an impact on the integrity and function of the blood-brain barrier (BBB) in human APOE-targeted replacement mice. Using the quantitative in situ brain perfusion technique, we first found lower (13.0% and 17.0%) brain transport coefficient (Clup) of [ 3 H]-diazepam in APOE4 mice at 4 and 12 months, compared with APOE2 and APOE3 mice, reflecting a decrease in cerebral vascularization. Accordingly, results from immunohistofluorescence experiments revealed a structurally reduced cerebral vascularization (26% and 38%) and thinner basement membranes (30% and 35%) in 12-month-old APOE4 mice compared with APOE2 and APOE3 mice, suggesting vascular atrophy. In addition, APOE4 mice displayed a 29% reduction in [ 3 H]-D-glucose transport through the BBB compared with APOE2 mice without significant changes in the expression of its transporter GLUT1 in brain capillaries. However, an increase of 41.3% of receptor for advanced glycation end products (RAGE) was found in brain capillaries of 12-month-old APOE4 mice. In conclusion, profound divergences were observed between APOE genotypes at the cerebrovascular interface, suggesting that APOE4-induced BBB anomalies may contribute to AD development.

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Section: Reduction Of Relative Vessel Density and Thinner Basementmentioning

confidence: 84%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Human Apolipoprotein E ε4 Expression Impairs Cerebral Vascularization and Blood—Brain Barrier Function in Mice

Alata

Yue

St‐Amour

et al. 2014

J Cereb Blood Flow Metab

Self Cite

136

104

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“…In situ cerebral perfusion (ISCP) technique was used as previously described 15 for the measurement of the distribution volume and the brain uptake coefficient (K in ) of IVIg. This technique ensures that 100% of the injected dose runs through the cerebral vasculature, avoiding peripheral distribution and metabolism.…”

Section: In Situ Cerebral Perfusionmentioning

confidence: 99%

“…15 This technique was performed by injecting (A-C) Spleen, liver, cortex, and hippocampus homogenates were prepared using five volumes of radio immunoprecipitation assay buffer/mg tissue. The quantification of hIgG and mIgG was performed using specific enzyme-linked immunosorbent assays.…”

Section: Apparent Competition Between Human Immunoglobulin G and Endomentioning

confidence: 99%

Brain Bioavailability of Human Intravenous Immunoglobulin and its Transport through the Murine Blood–Brain Barrier

St‐Amour

Paré

Alata

et al. 2013

J Cereb Blood Flow Metab

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151

119

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Intravenous immunoglobulin (IVIg) is currently evaluated in clinical trials for the treatment of various disorders of the central nervous system. To assess its capacity to reach central therapeutic targets, the brain bioavailability of IVIg must be determined. We thus quantified the passage of IVIg through the blood-brain barrier (BBB) of C57Bl/6 mice using complementary quantitative and qualitative methodologies. As determined by enzyme-linked immunosorbent assay, a small proportion of systemically injected IVIg was detected in the brain of mice (0.009 ± 0.001% of injected dose in the cortex) whereas immunostaining revealed localization mainly within microvessels and less frequently in neurons. Pharmacokinetic analyses evidenced a low elimination rate constant (0.0053 per hour) in the cortex, consistent with accumulation within cerebral tissue. In situ cerebral perfusion experiments revealed that a fraction of IVIg crossed the BBB without causing leakage. A dose-dependent decrease of brain uptake was consistent with a saturable blood-to-brain transport mechanism. Finally, brain uptake of IVIg after a subchronic treatment was similar in the 3xTg-AD mouse model of Alzheimer disease compared with nontransgenic controls. In summary, our results provide evidence of BBB passage and bioavailability of IVIg into the brain in the absence of BBB leakage and in sufficient concentration to interact with the therapeutic targets.

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Quantitative study of the capillaries within the white matter of the Tg2576 mouse model of Alzheimer's disease

et al. 2019

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Introduction To quantitatively investigate the capillaries within the white matter of Tg2576 Alzheimer's disease (AD) transgenic mice during the early stage. Methods In the current study, 10‐month‐old male Tg2576 AD mice were used as the early‐stage AD group and age‐matched nontransgenic littermate mice were used as the wild‐type group. Then, the Morris water maze was used to examine the spatial learning and memory abilities of the mice in both groups, and unbiased stereological methods were used to accurately quantify the volume of white matter and the parameters of the capillaries within the white matter, such as the total length, total volume, and total surface area of capillaries. Results The Morris water maze performance of the Tg2576 group was worse than that of the wild‐type group, while the white matter volume did not significantly differ between the wild‐type group and the Tg2576 group. The total length, total volume, and total surface area of the capillaries within the white matter of the Tg2576 group were significantly decreased compared to those of the wild‐type group. Conclusions The current study provide structural basis for understanding the pathological changes of the early stage of AD and cognitive decline in AD might be associated with changes in the white matter capillaries. Capillaries within the white matter might, thus, serve as a valid target for the prevention and treatment of early‐stage AD.

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Reduction of the cerebrovascular volume in a transgenic mouse model of Alzheimer's disease

Cited by 94 publications

References 40 publications

Human Apolipoprotein E ε4 Expression Impairs Cerebral Vascularization and Blood—Brain Barrier Function in Mice

Human Apolipoprotein E ε4 Expression Impairs Cerebral Vascularization and Blood—Brain Barrier Function in Mice

Brain Bioavailability of Human Intravenous Immunoglobulin and its Transport through the Murine Blood–Brain Barrier

Quantitative study of the capillaries within the white matter of the Tg2576 mouse model of Alzheimer's disease

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