Increased Expression of Renal Drug Transporters in a Mouse Model of Familial Alzheimer's Disease

Pan, Yijun; Omori, Kotaro; Ali, Izna; Tachikawa, Masanori; Brouwer, Kim L.R.; Nicolazzo, Joseph A.

doi:10.1016/j.xphs.2019.02.016

Cited by 13 publications

(14 citation statements)

References 38 publications

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“…In addition to altered transporter abundance at the small intestine, we also recently reported that the renal abundance of Mrp2, organic anion transporter 3, and organic cation transporter 2 were significantly higher in APP/PS1 mice relative to WT mice. 14 Taken together, these results indicate that the processes governing intestinal absorption, metabolism, and renal excretion are likely to be affected in AD.…”

Section: ■ Introductionmentioning

confidence: 80%

“…25,26 ■ MATERIALS AND METHODS Materials. 14 C-mannitol, 14 C-caffeine, 3 H-digoxin, and 3 Hdiazepam were obtained from American Radiolabeled Chemicals (Saint Louis, MO). Ultima Gold liquid scintillation cocktail was purchased from PerkinElmer (Boston, MA).…”

Section: ■ Introductionmentioning

confidence: 99%

“…Both plasma and brain samples were stored at −20 °C until analysis for drug quantification by the developed and validated HPLC or LC-MS/MS assays (Supporting Information). The concentration of each of the probe compounds in brain parenchyma was corrected for cerebral vascular contamination using a microvascular volume that we previously determined in C57BL/6J mice using 14 Cinulin (i.e., 0.017 mL/g). 28 It should be noted that this vascular volume is similar to the vascular volume reported in 3×Tg AD mice (another mouse model of AD).…”

Section: ■ Introductionmentioning

confidence: 99%

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Intestinal Permeability and Oral Absorption of Selected Drugs Are Reduced in a Mouse Model of Familial Alzheimer’s Disease

et al. 2020

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Compared with the significant number of studies reporting altered abundance and function of drug transporters at the blood–brain barrier (BBB) in Alzheimer’s disease (AD), the impact of AD on the abundance of intestinal drug transporters and the subsequent effects on oral drug absorption have received little attention. We have reported the altered abundance of some small intestinal drug transporters in a familial mouse model of AD; however, whether this leads to altered oral drug absorption is unknown. The current study examined plasma concentrations of caffeine and diazepam (markers for transcellular passive transport), digoxin (P-glycoprotein substrate), and valsartan (multidrug resistance-associated protein 2 substrate) following oral administration to 8–10 month old female wild-type (WT) and APPswe/PSEN1dE9 (APP/PS1) transgenic mice, a commonly used mouse model of familial AD. The plasma exposure of valsartan and digoxin was significantly (p < 0.05) lower in APP/PS1 animals compared with WT mice, whereas the plasma concentrations of the passive transcellular markers caffeine and diazepam did not significantly differ between the two genotypes. To assess whether the reduced oral absorption of valsartan and digoxin was due to decreased intestinal transport, the ex vivo transport of the previously mentioned drugs and mannitol (a marker of paracellular transport) across the jejunum of WT and APP/PS1 mice was assessed over 120 min. In line with the in vivo absorption studies, the permeability of caffeine and diazepam did not significantly differ between WT and APP/PS1 mice. The permeability of 3H-digoxin through the APP/PS1 mouse jejunum was lower than that measured through the WT jejunum; the average amount (relative to dose applied) permeating the tissue over 120 min was 0.22 ± 0.11% (mean ± SD) for the APP/PS1 jejunum and 0.85 ± 0.3% for the WT jejunum. A 1.9-fold reduction in the average amount of valsartan permeating the jejunum of APP/PS1 mice relative to that of WT mice was also detected. Although no apparent morphological alterations were observed in the jejunal tissue of APP/PS1 mice, the permeability of 14C-mannitol across the jejunum from APP/PS1 mice was lower than that across the WT jejunum (P app= 10.7 ± 3.7 × 10–6 and 6.0 ± 3.4 × 10–6 cm/s, respectively), suggesting tightened paracellular junctions in APP/PS1 mice. These studies are the first to demonstrate, in APP/PS1 mice, reduced intestinal permeability and the absorption of drugs commonly prescribed to people with AD for their comorbidities. If these findings translate to people with AD, then modified dosing regimens may be necessary for selected drugs to ensure that their plasma concentrations remain in the effective range.

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Section: ■ Introductionmentioning

confidence: 80%

Section: ■ Introductionmentioning

confidence: 99%

Section: ■ Introductionmentioning

confidence: 99%

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Intestinal Permeability and Oral Absorption of Selected Drugs Are Reduced in a Mouse Model of Familial Alzheimer’s Disease

et al. 2020

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“…However, in an OAT1-deficient AD mouse model, learning-and memory-related behavior deficiency, reduced LTP levels and higher soluble Aβ concentrations in the early stage were increased compared with the corresponding levels in control tg2576 mice, suggesting that OAT1 may affect the AD process [77]. In addition, Oat3 and Oct2 protein expression levels were increased 1.3-and 1.4-fold, respectively, in the kidneys of APP/PS1 transgenic mice compared with those in wild-type mice, which may have affected drug elimination in this AD model [78].…”

Section: Other Uptake Transporters and Admentioning

confidence: 87%

Alteration in the Function and Expression of SLC and ABC Transporters in the Neurovascular Unit in Alzheimer’s Disease and the Clinical Significance

Jia¹,

Wang²,

Zhang³

et al. 2020

Aging and disease

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The neurovascular unit (NVU) plays an important role in maintaining the function of the central nervous system (CNS). Emerging evidence has indicated that the NVU changes function and molecules at the early stage of Alzheimer's disease (AD), which initiates multiple pathways of neurodegeneration. Cell types in the NVU have become attractive targets in the interventional treatment of AD. The NVU transportation system contains a variety of proteins involved in compound transport and neurotransmission. Brain transporters can be classified as members of the solute carrier (SLC) and ATP-binding cassette (ABC) families in the NVU. Moreover, the transporters can regulate both endogenous toxins, including amyloid-beta (Aβ) and xenobiotic homeostasis, in the brains of AD patients. Genome-wide association studies (GWAS) have identified some transporter gene variants as susceptibility loci for late-onset AD. Therefore, the present study summarizes changes in blood-brain barrier (BBB) permeability in AD, identifies the location of SLC and ABC transporters in the brain and focuses on major SLC and ABC transporters that contribute to AD pathology.

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“…However, data suggest that AD also has systemic effects on the body. It is known, from AD models in rodents, that AD impairs the function of peripheral organs such as liver, kidney, and small intestine (González-Domínguez et al 2015b ; Pan et al 2019 ). Metabolomic results from APP/PS1 mouse models revealed that the liver was the organ first affected during the progression of amyloid pathology, demonstrating impaired energy metabolism, amino acid metabolism, nucleic acid metabolism, as well as ketone and fatty acid metabolism (Zheng et al 2019 ).…”

Section: Discussionmentioning

confidence: 99%

Exercise combined with a probiotics treatment alters the microbiome, but moderately affects signalling pathways in the liver of male APP/PS1 transgenic mice

et al. 2020

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It has been demonstrated that physical exercise and probiotic supplementation delay the progress of Alzheimer’s Disease (AD) in male APP/PS1TG mice. However, it has also been suggested that both exercise and AD have systemic effects. We have studied the effects of exercise training and probiotic treatment on microbiome and biochemical signalling proteins in the liver. The results suggest that liver is under oxidative stress, since SOD2 levels of APP/PS1 mice were decreased when compared to a wild type of mice. Exercise training prevented this decrease. We did not find significant changes in COX4, SIRT3, PGC-1a or GLUT4 levels, while the changes in pAMPK/AMPK, pmTOR/mTOR, pS6/S6 and NRF2 levels were randomly modulated. The data suggest that exercise and probiotics-induced changes in microbiome do not strongly affect mitochondrial density or protein synthesis-related AMPK/mTOR/S6 pathways in the liver of these animals.

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Increased Expression of Renal Drug Transporters in a Mouse Model of Familial Alzheimer's Disease

Cited by 13 publications

References 38 publications

Intestinal Permeability and Oral Absorption of Selected Drugs Are Reduced in a Mouse Model of Familial Alzheimer’s Disease

Intestinal Permeability and Oral Absorption of Selected Drugs Are Reduced in a Mouse Model of Familial Alzheimer’s Disease

Alteration in the Function and Expression of SLC and ABC Transporters in the Neurovascular Unit in Alzheimer’s Disease and the Clinical Significance

Exercise combined with a probiotics treatment alters the microbiome, but moderately affects signalling pathways in the liver of male APP/PS1 transgenic mice

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