Regional transport of TNF-α across the blood-brain barrier in young ICR and young and aged SAMP8 mice
Introduction
The blood-brain barrier (BBB) is a major regulatory interface between the central nervous system (CNS) and the peripheral circulation. In addition to limiting the passage of serum proteins into the CNS, it also controls the entry of vitamins, electrolytes, and nutrients [12]. More recently, it has been shown that the BBB controls the exchange of peptides and regulatory proteins between the CNS and blood [4]. The ability of the BBB to control the exchange of regulatory substances between the blood and CNS suggests a role of the BBB in brain-peripheral tissue communication. For example, transport of leptin across the BBB affects body weight [6], [19] and pituitary adenylate cyclase activating polypeptide is transported in quantities sufficient to exert neuroprotective effects [42].
Tumor necrosis factor-α (TNF) is also transported across the BBB [22]. Blood-borne TNF has a wide range of effects on the CNS, including effects on appetite, temperature regulation, and body weight [37] and TNF promotes some of the pathologic events of Alzheimer’s disease [30], [33]. Therefore, TNF originating from the circulation could act within the CNS to accelerate Alzheimer’s disease.
The BBB undergoes changes with aging and in Alzheimer’s disease [13], [15], [24], [25]. However, only a few of the numerous saturable systems which transport substances across the BBB have been investigated for changes in aging or Alzheimer’s disease. These studies show that some of these saturable transport systems, including those for regulatory substances, are altered [3], [11], [20], [23], [40]. Amyloid beta protein (Aβ) could be responsible for some of these changes, especially those seen in Alzheimer’s disease. Aβ adheres to the capillaries which comprise the BBB, is transported across the BBB, and can alter proliferation and various functions of brain endothelial cells [8], [16], [21], [28], [43]. TNF also alters the function of the BBB and with long-term exposure can even lead to disruption of the BBB [14], [27].
The BBB transporter for TNF is altered in other disease states. For example, saturable transport across the BBB is enhanced in mice with experimental allergic encephalomyelitis, an animal model of multiple sclerosis [36]. TNF transport is also increased in the traumatically injured spinal cord [35]. We, therefore, examined whether TNF transport was altered in aged SAMP8 mice. The SAMP8 mouse is a natural mutation that develops severe learning and memory disorders by 12 months of age, coinciding with an overexpression of amyloid precursor peptide and an increase in brain levels of Aβ [17], [18], [34]. Alterations in TNF transport in this strain of mouse would suggest that Aβ could underlie those changes and would raise the possibility that similar changes might take place in Alzheimer’s disease.
Section snippets
Methods
Radioactive Labeling: Recombinant murine TNF-α purchased from R&D (Minneapolis, MN) was radioactively labeled with 131I (I-TNF) by the enzymobead method. The I-TNF was separated from unincorporated 131I on a column of G-10 Sephadex. The specific activity was about 700 Ci/mmol.
Transport Rates
Young (2 mo old) ICR mice and young (2 mo old) and aged (17 mo old) SAMP8 mice from our in-house colonies were anesthetized with ethyl carbamate and the left jugular vein and right carotid artery exposed. Mice were given an injection into the jugular vein of 0.2 ml of lactated Ringer’s solution containing 1% bovine serum albumin (LR-BSA) and about 106 cpm (0.64 pmol) of I-TNF. Mice were maintained under a heat lamp before and after the iv injection and monitored for respiratory difficulty.
Statistics
The values for Ki were compared by analysis of variance (ANOVA) to determine whether there were differences within groups. This was followed by Newman-Keuls post test to determine which values within a group differed. The standard deviation of the mean for the slope was taken as the SE and, because two means (the slope and the intercept) were calculated from the data, n − 1 was used as the n value in the ANOVA and range tests. Differences among brain regions were tested individually for ICR,
Results
In ICR mice, the transport rate for I-TNF into whole brain was 0.293 ± 0.047 μl/g-min (Fig. 1). The transport rate varied regionally Fig. 1, Fig. 2 from a low of 0.189 ± 0.28 μl/g-min in the parietal cortex (not statistically different from whole brain) to a high of 1.73 ± 0.331 μl/g-min in the hypothalamus (p < 0.001 when compared to whole brain). The occipital cortex also had a transport rate (1.01 ± 0.345 μl/g-min) that was significantly higher (p < 0.05) than that of whole brain. Table 1
Discussion
These studies show that the rate at which TNF is transported across the BBB varies among regions of the brain. Within the SAMP8 strain, differences also occurred between young and aged mice. No strain differences, however, were noted when young ICR and young SAMP8 mice were compared.
Multiple-time regression analysis was used here to measure Ki. This is a highly sensitive method that can even measure the residual leakiness of the BBB to substances traditionally used as vascular markers, such as
Acknowledgements
This work was supported by VA Merit Review, R0-1 MH54979, and R0-1 NS41863.
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