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The Journals of Gerontology Series A: Biological Sciences and Medical Sciences 55:B601-B606 (2000)
© 2000 The Gerontological Society of America

Permeability of the Blood-Brain Barrier to Albumin and Insulin in the Young and Aged SAMP8 Mouse

William A. Banksa, Susan A. Farra and John E. Morleya

a GRECC, Veterans Affairs Medical Center–St. Louis and Saint Louis University School of Medicine, Division of Geriatrics, Department of Internal Medicine, Missouri

William A. Banks, 915 N. Grand Blvd., St. Louis, MO 63106 E-mail: bankswa{at}slu.edu.

Decision Editor: John A. Faulkner, PhD


   Abstract
Top
 Abstract
Methods
 Results
 Discussion
 References
 
The decrease in the insulin cerebrospinal fluid/serum ratio seen in Alzheimer's disease has been suggested as a mechanism by which brain glucose utilization could be perturbed. Insulin is transported across the blood-brain barrier (BBB) by a system that is altered by pathophysiological events. We used SAMP8 mice, a strain that by 8–12 months of age develops severe deficits in learning and memory, to determine whether the insulin transporter or BBB integrity was altered with aging. BBB integrity was measured by injecting radioactive albumin intravenously, washing out the vascular space up to 17 hours later, and measuring brain/serum ratios. This very sensitive method found no increase in the permeability of the BBB to albumin in young and aged SAMP8 mice. This compares with previous studies in humans with Alzheimer's disease and in other colonies of SAMP8 mice that have found evidence for BBB disruption. For radioactively labeled insulin, we used multiple-time regression analysis to measure both the unidirectional influx rate (Ki) and the reversible binding to brain endothelium (Vi). A nonsignificant decrease in the transport rate for whole brain occurred in aged SAMP8 mice. Ki and Vi values significantly varied among brain regions and the Ki for the thalamus and the Vi for the cerebellum and thalamus were higher in aged mice. We conclude that alterations in BBB integrity or the activity of the BBB insulin transporter do not underlie the deficits in learning and memory seen in the aged SAMP8 mouse.

THE blood-brain barrier (BBB) acts as the regulatory interface by controlling the rate of exchange of substances between the central nervous system (CNS) and the blood. As such, the BBB serves homeostatic, nutritive, and communicative roles. Alteration in BBB integrity or in its higher functions can result in dysfunction and disease of the CNS. Previous reports have suggested that the BBB may be impaired in Alzheimer's disease. Some reports suggest that the BBB is disrupted, allowing serum proteins increased entry into the CNS (1) (2), whereas other reports have failed to find such changes (3) (4) (5). Brain endothelial cells, which constitute the BBB, derived from patients with Alzheimer's disease have increased nitric oxide synthase activity and decreased phosphokinase activity, secrete neurotoxic factors, and transport glucose less rapidly (4) (6) (7) (8) (9)

An altered cerebrospinal fluid (CSF)/serum ratio of insulin in Alzheimer's disease has been reported previously (10) (11). Such altered ratios, as exemplified by the ratio for leptin in obesity (12) (13), can indicate impaired transport across the BBB (14). Other aspects of insulin action altered in Alzheimer's disease include increased levels of serum insulin, increased or decreased levels of insulin in the CSF, and decreased levels of insulin, C-peptide, and insulin receptors in the brain (10) (11) (15) (16). Insulin has been reported to improve memory independently of its effects on levels of serum glucose in patients with Alzheimer's disease (17).

Insulin receptors occur throughout the brain (18) (19), and CNS insulin has been shown to decrease hypothalamic levels of neuropeptide Y, decrease feeding, increase serum glucose levels, increase sympathetic outflow, and decrease serum insulin (20) (21) (22) (23) (24) (25). Insulin was originally believed not to cross the BBB (26), but subsequently passage was shown by way of a saturable transport system (27) (28). Binding sites that likely represent transporters are found both on brain capillaries (29) (30) (31) and on the choroid plexus (18) (19) (32), and insulin enters most areas of the brain (33) (34). The saturable transporter for insulin is altered physiologically and by disease. For example, insulin transport into the brain changes seasonally in hibernating animals (35) and is affected by diabetes mellitus in mice (36).

Any alterations in the function of the BBB in Alzheimer's disease could be mediated by amyloid ß protein (Aß). This amnestic (37) has been postulated to have a causative role in Alzheimer's disease (38) (39). Recently, vaccinating against Aß in mice that overexpress its precursor, amyloid precursor protein (APP), reduces the occurrence of neuropathologic changes resembling those seen with Alzheimer's disease (40). Aß and its degradation products cross the BBB poorly unless bound to ApoJ (41) (42) (43) (44) (45), but Aß readily binds to (41) (43), is associated with (46) (47), and is cleaved by (48) (49) the brain endothelial cells which constitute the BBB. Aß has been shown to inhibit brain endothelial cell proliferation and induce apoptosis, decrease lectin binding sites, impair BBB integrity, stimulate monocyte diapedesis, be associated with microvascular angioarchitectural changes, and impair glucose transport across the BBB (47) (50) (51) (52) (53) (54).

The SAMP8 mouse offers a model in which to study the interactions of impairments in learning and memory and aging. At 4 months, these mice exhibit normal learning and memory but by 12 months of age have severe cognitive deficits (55) (56) (57). We, therefore, determined whether the integrity of the BBB and whether the transport of insulin across the BBB were altered with aging in SAMP8 mice.


   Methods
Top
 Abstract
 Methods
Results
 Discussion
 References
 
Radioactive Labeling
Human serum albumin was radioactively labeled with 131I (I-Alb) by the chloramine T method and purified on a G-10 sephadex column. Insulin was radioactively labeled with 131I (I-Ins) by the chloramine T method and purified on a G-10 sephadex column. The specific activity of the I-Ins was 55 Ci/g.

Measurement of BBB Integrity With Albumin
Mice were anesthetized with urethane and the left and right jugular veins isolated. Mice received an injection into the left jugular vein of 0.2 ml of lactated Ringer's solution with 1% bovine serum albumin (LR-BSA) containing about 107 cpm of I-Alb. Between 0.5 hour and 17 hours after injection, blood was collected from the abdominal aorta and the vascular space of the brain washed free of blood by severing both jugular veins, opening the thorax, clamping the descending thoracic aorta, and perfusing 20 ml of lactated Ringer's solution through the left ventricle of the heart. The mouse was decapitated and the brain removed. The blood was centrifuged at 5000 x g for 10 minutes at 4°C and the level of radioactivity in 50 µl of serum was determined in a gamma counter. The brain was dissected into 10 regions (frontal cortex, parietal cortex, occipital cortex, cerebellum, midbrain, hippocampus, thalamus, hypothalamus, striatum, and pons-medulla) after the method of Glowinski and Iversen (58). Each region was weighed and its level of radioactivity determined in a gamma counter. The brain/serum ratio for the I-Alb was computed in units of µl/g of brain.

The unidirectional influx constant (Ki) was computed by multiple-time regression analysis. The brain/serum ratios are plotted against their respective exposure times (Expt). Expt was calculated from the formula:

(1)
where Cpt is the level of radioactivity in serum at time t. Exposure time corrects for the clearance of I-Alb from the blood. The Ki with its error term is measured as the slope for the linear portion of the relation between the ratios and Expt. The y intercept of the linear relation measures Vi, the distribution volume in brain at t = 0.

Measurement of Insulin Uptake
Young and aged SAMP8 mice were anesthetized with urethane and the left jugular vein and right carotid artery exposed. Mice were given an injection into the jugular vein of 0.2 ml of LR-BSA containing about 107 cpm of I-Ins. Carotid artery blood and the whole brain were obtained between 1 and 10 minutes after the intravenous injection. The brain was dissected as described above and the levels of radioactivity in the arterial serum and brain regions were determined as above. The brain/serum ratios were computed and the Ki and Vi were determined by multiple-time regression analysis as described above.

Statistics
Means are expressed with the standard errors. Means were compared by analysis of variance (ANOVA) followed by Newman-Keuls post-test. Slopes, intercepts, and their error terms were computed with Prism 3.0 software (GraphPad Inc, San Diego, CA) and compared by ANOVA followed by Newman-Keuls post-test.


   Results
Top
 Abstract
 Methods
 Results
Discussion
 References
 
BBB Permeability to I-Alb
A correlation existed between whole brain/serum ratios and Expt for I-Alb in young SAMP8 mice (n = 9, r = .684, p < .05). The Ki was 0.0315 µl/g-min, demonstrating a slow rate of passage of I-Alb across the BBB, and the Vi was 1.09 µl/g. For aged SAMP8 mice, no correlation existed for I-Alb between whole brain/serum ratios and Expt. Three brain regions in the young SAMP8 mice showed significant uptake of I-Alb over time, but no region in aged SAMP8 mice showed any uptake. These three regions were the cerebellum (Ki = 0.0449 µl/g-min, Vi = 0.863 µl/g, n = 9, r = 0.752, p < .05), the hippocampus (Ki = 0.0584 µl/g-min, Vi = 1.03 µl/g, n = 9, r = 0.764, p < .05), and the pons-medulla (Ki = 0.0659 µl/g-min, Vi = 0.944 µl/g, n = 9, r = 0.813, p < .01). No statistical difference occurred between young and aged mice when their ratios versus Expt relations were compared. The results were also analyzed by combining the ratios for all time points to produce a mean brain region/serum ratio (Table 1 ). No significant differences occurred among brain regions or for a given brain region between young and aged mice.


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  		Table 1. I-Alb Present in Each Brain Region (µl/g)

 
The brains of the aged SAMP8 mice weighed 524 ± 14.2 mg (n = 7), which was about 8% more than the 483 ± 8.5 mg (n = 9) that the brains of the young mice weighed and was a statistically significant difference: F(1,15) = 6.43, p < .05 (Table 2 ). To further compare brain weight differences between young and aged mice, the weight of each brain region was expressed as a percentage of total brain weight. The frontal cortex (young: 22.0 ± 0.97% of whole brain weight; aged: 18.3 ± 0.90%; F[1,15] = 7.63, p < .05) and the whole cortex (young: 45.7 ± 1.11%; aged: 42.6 ± 0.57%; F(1,15) = 5.67, p < .05) were found to be relatively smaller in the aged mice.


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  		Table 2. Regional Brain Weights Expressed as Percentage of Whole Brain Weight

 
Insulin Uptake
A statistically significant relation existed between the whole brain/serum ratio and Expt for both young (Ki = 0.447 ± 0.147 µl/g-min, Vi = 12.2 ± 1.24, r = 0.779, n = 8, p < .05) and aged (Ki = 0.369 ± 0.138, Vi = 14.4 ± 1.26, r = 0.709, n = 9, p < .05) SAMP8 mice ( Fig. 1). No statistically significant difference existed between the values for Ki but there was a trend (p < .10) for a difference in the values for Vi.



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  		Figure 1. Comparison of uptake of I-Ins by brain in young and aged SAMP8 mice. No difference occurred in the rate of uptake but a trend (.05 < p < .10) existed for differences in the intercept.

 
Statistically significant relations existed between brain region/serum ratios and Expt for whole cortex, frontal cortex, parietal cortex, cerebellum, striatum, thalamus, and midbrain in both young and aged SAMP8 mice and for hippocampus and hypothalamus in aged mice. Insulin uptake could not be demonstrated for the occipital cortex or the pons-medulla in young and aged mice or for the hippocampus or hypothalamus in young mice.

The Prism software was used to compare the regression lines describing insulin uptake between young and aged mice for the various brain regions. The Ki values for brain regions showed no differences between young and aged mice. Differences did exist for the Vi values between young and aged mice ( Fig. 2) for the regions of the cerebellum (F[1,10] = 13.4, p < .005), parietal cortex (F[1,13] = 4.84, p < .05), and thalamus (F[1.10] = 22.6, p < .005). Table 3 shows the values for Vi in young and aged mice.



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  		Figure 2. Comparison of uptake of I-Ins by brain regions in young and aged SAMP8 mice. The Vi for parietal cortex, thalamus, and cerebellum was higher in aged than in young mice.

 

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  		Table 3. Values for Vi (µl/g) ± Error Term

 
ANOVA was used to compare the Ki or the Vi values among brain regions within the groups of young or aged mice. The error terms for Ki and Vi produced by Prism software were treated as standard errors of the mean and the n reduced by one to adjust the degrees of freedom. The ANOVA for Ki showed no differences among brain regions for either the young or the aged groups. The ANOVA for Vi in young mice was significant (F[6,45] 8.50, p < .005) and Newman-Keuls showed that the whole brain value was greater than the values for thalamus (p < .01) and striatum (p < .05) and less than the value for cerebellum (p < .05). For aged mice, the ANOVA showed significant differences among the brain region values for Vi (F[8,59] = 4.63, p < .05) and the value for whole brain was greater than that for thalamus (p < .05) or striatum (p < .05). Table 4 summarizes differences among other brain regions for young and aged mice.


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  		Table 4. Differences in Vi by Brain Region and Age

 

   Discussion
Top
 Abstract
 Methods
 Results
 Discussion
References
 
These findings show that the BBB is not disrupted in aged SAMP8 mice. Controversy exists regarding disruption or lack of disruption of the BBB in Alzheimer's disease (1) (2) (4) (5). CSF/serum ratios for endogenous serum proteins such as albumin, often used to assess BBB integrity, have been found to be elevated in Alzheimer's disease. However, such ratios represent a steady state that is affected by other parameters, such as the CSF reabsorption rate. Acute assessment with administered protein, therefore, has the advantage of being able to measure influx rate as a pure parameter.

Disruption of the BBB can be dramatic, as in the case of tumor invasion of the brain, or very subtle, as in the case of epinephrine-induced hypertension (59) (60). We designed the current experiment to detect extremely subtle changes in BBB function. First, we measured uptake over a 17-hour period. This increases the sensitivity of detecting low permeability rates. Second, we washed out the vascular space of the brain with buffer. This removes all the albumin from the brain that has not crossed the BBB. However, despite this design, passage of albumin across the BBB was barely detectable in young mice. The influx constant measured, 0.0315 µl/g-min [5.25(10-7) ml/g-min], agrees very well with the influx rates previously measured for vascular markers (61). In comparison, the relation between brain/serum ratios and exposure time was not statistically significant for aged mice and so passage of albumin across the BBB could not be demonstrated. When the brain/serum ratios for albumin were combined for all times, no difference could be detected between young and aged mice (Table 1 ). Therefore, these results failed to show that aged SAMP8 mice have a disruption of the BBB to serum albumin.

Previous studies have found disruption of the BBB in colonies of SAMP8 mice (62) (63) (64). These disruptions are localized and not of a great magnitude, but are demonstrable. It has been speculated that aging renders the BBB more sensitive to disruption by various insults (65). It may be that the disruption noted in other colonies of SAMP8 mice is due to some other insult such as the viral infections thought to be present in those colonies but absent from our colony of SAMP8 mice.

As an incidental finding, our study found differences in brain weight between young and aged SAMP8 mice. An increased brain weight with aging is to be expected in mice. The aged SAMP8 mice had a relative decrease in the weight of whole and frontal cortex (Table 2 ). This corresponds to morphometric changes recently described in the neocortex of the related SAMP10 strain (66). Whether this relative loss of cortex is related to the deficits in learning and memory is unclear (67).

Insulin was transported across the BBB in both young and aged SAMP8 mice ( Fig. 1). Insulin is known to cross the BBB by a saturable transport system (27) (28). Both brain endothelial cells and the choroid plexus bind insulin, suggesting that insulin crosses both the endothelial and the epithelial (blood-CSF) barriers (18) (19) (29) (30) (31) (32). The capillary depletion method has shown that I-Ins crosses the BBB completely and the radioactivity recovered from the CNS after intravenous injection is intact I-Ins (27). The insulin transporter appears to be a regulated system, because it is shut off during hibernation and altered with fasting and diabetes mellitus (35) (36). The function of other transporters located at the BBB, including those regulatory peptides, are decreased in aging (68) (69) (70) (71). Therefore, the postulate that the decrease in insulin within the CNS seen in Alzheimer's disease was due to an alteration in transport function is a logical one. The decrease in transport of insulin for whole brain did not reach statistical significance between young and aged mice and the values for Ki did not differ for brain regions ( Fig. 1). Therefore, an age-related alteration in transport rate is unlikely to be the explanation for the lower level of insulin within the CNS.

The Vi differed between young and aged mice for the parietal cortex, cerebellum, and thalamus ( Fig. 2; Table 3 ). Differences for Vi occurred when values for brain regions were compared with whole brain or with each other (Table 4 ). The Vi may represent insulin that is bound to, but not internalized by, the brain endothelial cell. Such binding would likely reflect uptake not by insulin transporters but by insulin receptors, that is, binding sites involved in signal transduction. Insulin can alter brain endothelial functions not directly related to glucose transport (72). Regional variation in insulin receptors would suggest regional differences in the effects of insulin on those endothelial functions.

Not all areas of the brain transported insulin. The occipital cortex and the pons-medulla of both young and aged mice did not appear to transport insulin. A previous study showed that for the ICR strain of mouse, the occipital cortex, midbrain, and thalamus did not transport insulin. The pons-medulla had the highest transport rate of any region in the ICR mouse. Therefore, among different strains of mice, such as ICR and SAMP8 mice, differences likely exist in the transport rate for insulin.

In conclusion, we found here that the BBB remains intact to serum albumin in the aged SAMP8 mouse. Insulin transport as measured by Ki and endothelial cell binding as measured by Vi shows significant regional variation, but minimal effects with aging. We conclude that alterations in BBB integrity or the activity of the BBB insulin transporter do not underlie the deficits in learning and memory seen in the aged SAMP8 mouse.


   Acknowledgments
 
We thank Cong Li and Cecelia Clever for technical assistance. This research was supported by VA Merit Review and NIMH R01-MH54979-01. Part of the data presented here was published in The Gerontological Society of America's 1999 Annual Scientific Meeting abstract volume, The Gerontologist. 1999;39(special issue I): 188.

Received January 10, 2000

Accepted June 12, 2000


   References
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 Abstract
 Methods
 Results
 Discussion
 References
 

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