Altered Brain Uptake of Therapeutics in a Triple Transgenic Mouse Model of Alzheimer’s Disease

Mehta, Dharmini; Short, Jennifer Lynn; Nicolazzo, Joseph A.

doi:10.1007/s11095-013-1116-2

Cited by 56 publications

(70 citation statements)

References 44 publications

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“…We and others previously showed that P-gp protein expression and transport activity are reduced in human A␤-overexpressing AD mouse models (Hartz et al, 2010;Mehta et al, 2013). These data are supported by studies with postmortem human brain tissue that demonstrate P-gp expression and activity levels are lower in the neurovasculature from patients with mild cognitive impairment and AD compared with those in age-matched, healthy individuals (Wijesuriya et al, 2010;Jeynes and Provias, 2011;van Assema et al, 2012;Deo et al, 2014).…”

Section: Discussionmentioning

confidence: 90%

“…Studies show that P-glycoprotein (P-gp), an efflux transporter in the luminal plasma membrane of brain capillaries, is critical for clearing A␤ from brain into blood (Lam et al, 2001;Cirrito et al, 2005;Kuhnke et al, 2007;Hartz et al, 2010). We and others showed that P-gp protein expression and transport activity levels are reduced in brain capillaries from AD mouse models, suggesting a link between high A␤ levels and reduced levels of brain capillary P-gp (Hartz et al, 2010;Mehta et al, 2013).…”

Section: Introductionmentioning

confidence: 91%

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Aβ40 Reduces P-Glycoprotein at the Blood–Brain Barrier through the Ubiquitin–Proteasome Pathway

Zhong²,

et al. 2016

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Failure to clear amyloid-␤ (A␤) from the brain is in part responsible for A␤ brain accumulation in Alzheimer's disease (AD).A critical protein for clearing A␤ across the blood-brain barrier is the efflux transporter P-glycoprotein (P-gp) in the luminal plasma membrane of the brain capillary endothelium. P-gp is reduced at the blood-brain barrier in AD, which has been shown to be associated with A␤ brain accumulation. However, the mechanism responsible for P-gp reduction in AD is not well understood. Here we focused on identifying critical mechanistic steps involved in reducing P-gp in AD. We exposed isolated rat brain capillaries to 100 nM A␤40, A␤40, aggregated A␤40, and A␤42. We observed that only A␤40 triggered reduction of P-gp protein expression and transport activity levels; this occurred in a dose-and time-dependent manner. To identify the steps involved in A␤-mediated P-gp reduction, we inhibited protein ubiquitination, protein trafficking, and the ubiquitin-proteasome system, and monitored P-gp protein expression, transport activity, and P-gpubiquitin levels. Thus, exposing brain capillaries to A␤40 triggers ubiquitination, internalization, and proteasomal degradation of P-gp. These findings may provide potential therapeutic targets within the blood-brain barrier to limit P-gp degradation in AD and improve A␤ brain clearance.

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Section: Discussionmentioning

confidence: 90%

Section: Introductionmentioning

confidence: 91%

Aβ40 Reduces P-Glycoprotein at the Blood–Brain Barrier through the Ubiquitin–Proteasome Pathway

Zhong²,

et al. 2016

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“…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%

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

136

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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“…Animal models of AD (3xTg and Tg2576) have revealed a link between both Pglycoprotein 1 expression and activity in relation to disease progression (231,232). This evidence suggests that accumulation of the toxic form of Aβ can lead to downregulation of the P-glycoprotein 1 transporter.…”

Section: Atp-binding Cassette Transporter Familymentioning

confidence: 99%

Astrocytic transporters in Alzheimer's disease

Ugbode

Whalley

et al. 2017

Biochemical Journal

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Astrocytes play a fundamental role in maintaining the health and function of the central nervous system. Increasing evidence indicates that astrocytes undergo both cellular and molecular changes at an early stage in neurological diseases, including Alzheimer's disease (AD). These changes may reflect a change from a neuroprotective to a neurotoxic phenotype. Given the lack of current disease-modifying therapies for AD, astrocytes have become an interesting and viable target for therapeutic intervention. The astrocyte transport system covers a diverse array of proteins involved in metabolic support, neurotransmission and synaptic architecture. Therefore, specific targeting of individual transporter families has the potential to suppress neurodegeneration, a characteristic hallmark of AD. A small number of the 400 transporter superfamilies are expressed in astrocytes, with evidence highlighting a fraction of these are implicated in AD. Here, we review the current evidence for six astrocytic transporter subfamilies involved in AD, as reported in both animal and human studies. This review confirms that astrocytes are indeed a viable target, highlights the complexities of studying astrocytes and provides future directives to exploit the potential of astrocytes in tackling AD.

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Altered Brain Uptake of Therapeutics in a Triple Transgenic Mouse Model of Alzheimer’s Disease

Abstract: These studies systematically assessed the impact of AD on BBB drug transport in a relevant animal model, and have demonstrated a reduction in the brain uptake of passively-absorbed molecules in this mouse model of AD.

Cited by 56 publications

References 44 publications

Aβ40 Reduces P-Glycoprotein at the Blood–Brain Barrier through the Ubiquitin–Proteasome Pathway

Aβ40 Reduces P-Glycoprotein at the Blood–Brain Barrier through the Ubiquitin–Proteasome Pathway

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

Astrocytic transporters in Alzheimer's disease

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