Evaluation of chronic lead effects in the blood brain barrier system by DCE-CT

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Abstract

Background

Lead (Pb) is an environmental factor has been suspected of contributing to the dementia including Alzheimer’s disease (AD). Our previous studies have shown that Pb exposure at the subtoxic dose increased brain levels of beta-amyloid (Aβ) and amyloid plaques, a pathological hallmark for AD, in amyloid precursor protein (APP) transgenic mice, and is hypothesized to inhibit Aβ clearance in the blood- cerebrospinal fluid (CSF) barrier. However, it remains unclear how different levels of Pb affect Aβ clearance in the whole blood-brain barrier system. This study was designed to investigate whether chronic exposure of Pb affected the permeability of the blood-brain barrier system by using the Dynamic Contrast-Enhanced Computerized Tomography (DCE-CT) method.

Methods

DEC-CT was used to investigate whether chronic exposure of toxic Pb affected the permeability of the real-time blood brain barrier system.

Results

Data showed that Pb exposure increased permeability surface area product, and also significantly induced brain perfusion. However, Pb exposure did not alter extracellular volumes or fractional blood volumes of mouse brain.

Conclusion

Our data suggest that Pb exposure at subtoxic and toxic levels directly targets the brain vasculature and damages the blood brain barrier system.

Introduction

Alzheimer’s disease (AD) is one of the most common causes of dementia over the age of 65 years [1]. Aggregation of beta-amyloid (Aβ) in the brain extracellular space to form the insoluble plaques is a hallmark of AD [2], and aggregated Aβ can further stimulate hyperphosphorylation of tau leading to the formation of neurofibrillary tangles in nerve terminals [3]. In AD patients, Aβ is also found in the cerebrospinal fluid (CSF) circulating in brain ventricles, and in the interstitial fluid around neurons and glial cells [[4], [5], [6], [7]]. We and others have shown the role of the blood brain barrier system in regulating brain Aβ homeostasis [[8], [9], [10], [11]]. The blood brain barrier system includes two types of barriers that separate the blood circulation from brain functional structures, the blood-brain barrier (BBB) between blood and interstitial fluid as well as the blood-CSF barrier between blood and CSF. BBB leakage due to microvascular injury, thinning and discontinuities in the AD has been reported in literature [12]. In AD, disrupted BBB may cause the dysfunction of Aβ transport from brain to the peripheral circulation [13]. Additionally, choroid plexus may also be involved in AD etiology [[14], [15], [16]]. Studies have found that choroid plexus participates in brain amyloidosis and Aβ transport [14,15,17,18]. Brain autopsies of AD patients reveal an extensive accumulation of Aβ plaques in the choroid plexus [19,20].

Lead (Pb) is an environmental factor has been implicated in the development of AD and related dementias [[21], [22], [23], [24]]. Since the blood brain barrier system is the identified target of Pb toxicity [25], it is quite possible that Pb toxicity may affect the critical processes in the blood brain barrier system that regulate Aβ transport and metabolism. Our previous studies have shown that Pb exposure at the subtoxic dose significantly increased brain levels of Aβ and amyloid plaques in an amyloid precursor protein (APP) transgenic mouse model, Tg-SwDI mice, a mouse model widely used to study AD and amyloid pathogenesis [26,27], possibly by inhibiting Aβ clearance in the blood-CSF barrier [22,28]. Despite these findings, it remains unclear how different levels of Pb affect Aβ transport in the whole blood-brain barrier system.

Dynamic Contrast-Enhanced Computerized Tomography (DCE-CT) is a medical imaging technology that utilizes trace quantity of a contrast agent and the Stewart-Hamilton indicator dilution approach [29] to mathematically determine tracer dynamics. Typically, an iodinated based tracer in injected into the subjects venous circulation, and serial 3D images at regular intervals are acquired, thus permitting mathematical modeling of cerebral blood volume and microvascular permeability changes in both animal and human brains [30,31]. Moreover, this technique has been adapted for animal models to quantify cerebral blood flow and cerebral blood volume in brain tumor studies [[32], [33], [34], [35]], where the DCE-CT contrast agent Isovue-370 was employed because of its high molecular weight, lack of cell permeation, and diffusion limitation across the vascular wall. These physiochemical properties, combined with the kinetic modeling permits the estimate of permeability surface area product, delineation of cerebrovascular vessels, and underlying neural tissues, thus providing the dynamic information of blood supply in relation to the supporting tissue [33,35,36]. This technique has thus been widely used to evaluate permeability surface area product as a measure of blood brain barrier permeability in animal models [[37], [38], [39], [40]]. Importantly, this approach can be applied in research and clinical studies for AD, since it can detect the real-time blood brain barrier system permeability induced by extrinsic factors such as Pb. The current study seeks to investigate whether chronic exposure of toxic Pb affected the permeability of the real-time blood brain barrier system by using the above mentioned DCE-CT approach.

Section snippets

Materials and methods

Tg-SwDI mice [Jackson Laboratory, 22] were housed 3–5 per cage, fed ad libitum rodent chow (Envigo Teklad) and had free access to water. In all cases, mice were maintained in a 12-h light/dark cycle, where the room was maintained at 23 ± 2 °C (40 % relative humidity). Tg-SwDI mice at the time of experimentation were 8 weeks old and were randomly allocated to one of four groups. The experimental dosing regime was originally designed as four-week treatments. However, since Pb at the highest dose

Results and discussion

In this study, we demonstrated the feasibility of a clinically translatable imaging method, DCE-CT, which allows noninvasive monitoring and quantifying the real-time cerebral regional blood flow, blood volume, and the blood brain barrier system permeability simultaneously. Fitting of the individual time courses to the operational model described by Fig. 1 and Eqs. (1), (2), (3), (4) showed a high degree of fit with an average R2 of 0.832 ± 0.026 (N = 44). Analysis of residual error (i.e.

CRediT authorship contribution statement

Huiying Gu: Conceptualization, Methodology, Validation, Formal analysis, Investigation, Writing - original draft. Paul R. Territo: Conceptualization, Investigation, Methodology, Formal analysis, Writing - review & editing. Scott A. Persohn: Investigation, Methodology. Amanda A. Bedwell: Investigation, Methodology. Kierra Eldridge: Investigation, Methodology. Rachael Speedy: Investigation, Methodology. Zhe Chen: Methodology. Wei Zheng: Conceptualization, Investigation, Supervision, Funding

Declaration of Competing Interest

The authors report no declarations of interest.

Acknowledgments

This work was supported by NIH/NIEHS R01 ES027078 to W.Z and Y.D.

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