Dataset Information

Krohn2011 - Cerebral amyloid-β proteostasis regulated by membrane transport protein ABCC1

ABSTRACT: Krohn2011 - Cerebral amyloid-β proteostasis regulated by membrane transport protein ABCC1 This model is described in the article: Cerebral amyloid-β proteostasis is regulated by the membrane transport protein ABCC1 in mice. Krohn M, Lange C, Hofrichter J, Scheffler K, Stenzel J, Steffen J, Schumacher T, Brüning T, Plath AS, Alfen F, Schmidt A, Winter F, Rateitschak K, Wree A, Gsponer J, Walker LC, Pahnke J. J. Clin. Invest. 2011 Oct; 121(10): 3924-3931 Abstract: In Alzheimer disease (AD), the intracerebral accumulation of amyloid-β (Aβ) peptides is a critical yet poorly understood process. Aβ clearance via the blood-brain barrier is reduced by approximately 30% in AD patients, but the underlying mechanisms remain elusive. ABC transporters have been implicated in the regulation of Aβ levels in the brain. Using a mouse model of AD in which the animals were further genetically modified to lack specific ABC transporters, here we have shown that the transporter ABCC1 has an important role in cerebral Aβ clearance and accumulation. Deficiency of ABCC1 substantially increased cerebral Aβ levels without altering the expression of most enzymes that would favor the production of Aβ from the Aβ precursor protein. In contrast, activation of ABCC1 using thiethylperazine (a drug approved by the FDA to relieve nausea and vomiting) markedly reduced Aβ load in a mouse model of AD expressing ABCC1 but not in such mice lacking ABCC1. Thus, by altering the temporal aggregation profile of Aβ, pharmacological activation of ABC transporters could impede the neurodegenerative cascade that culminates in the dementia of AD. This model is hosted on BioModels Database and identified by: BIOMD0000000618. To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

OTHER RELATED OMICS DATASETS IN: PRJNA144101

DISEASE(S): Alzheimer's Disease

SUBMITTER: Felix Winter

PROVIDER: BIOMD0000000618 | BioModels | 2016-07-27

REPOSITORIES: BioModels

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Publications

Cerebral amyloid-β proteostasis is regulated by the membrane transport protein ABCC1 in mice.

Krohn Markus M Lange Cathleen C Hofrichter Jacqueline J Scheffler Katja K Stenzel Jan J Steffen Johannes J Schumacher Toni T Brüning Thomas T Plath Anne-Sophie AS Alfen Franziska F Schmidt Anke A Winter Felix F Rateitschak Katja K Wree Andreas A Gsponer Jörg J Walker Lary C LC Pahnke Jens J

The Journal of clinical investigation 20110901 10

In Alzheimer disease (AD), the intracerebral accumulation of amyloid-β (Aβ) peptides is a critical yet poorly understood process. Aβ clearance via the blood-brain barrier is reduced by approximately 30% in AD patients, but the underlying mechanisms remain elusive. ABC transporters have been implicated in the regulation of Aβ levels in the brain. Using a mouse model of AD in which the animals were further genetically modified to lack specific ABC transporters, here we have shown that the transpor ...[more]

PMID: 21881209

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Project description:Qosa2014 - Mechanistic modeling that describes Aβ clearance across BBB Qosa2014 - Mechanistic modeling that describes Aβ clearance across BBB. Encoded non-curated model. Issues: - Confusing equation 6 - Missing initial values for spices This model is described in the article: Differences in amyloid-? clearance across mouse and human blood-brain barrier models: kinetic analysis and mechanistic modeling. Qosa H, Abuasal BS, Romero IA, Weksler B, Couraud PO, Keller JN, Kaddoumi A. Neuropharmacology 2014 Apr; 79: 668-678 Abstract: Alzheimer's disease (AD) has a characteristic hallmark of amyloid-? (A?) accumulation in the brain. This accumulation of A? has been related to its faulty cerebral clearance. Indeed, preclinical studies that used mice to investigate A? clearance showed that efflux across blood-brain barrier (BBB) and brain degradation mediate efficient A? clearance. However, the contribution of each process to A? clearance remains unclear. Moreover, it is still uncertain how species differences between mouse and human could affect A? clearance. Here, a modified form of the brain efflux index method was used to estimate the contribution of BBB and brain degradation to A? clearance from the brain of wild type mice. We estimated that 62% of intracerebrally injected (125)I-A?40 is cleared across BBB while 38% is cleared by brain degradation. Furthermore, in vitro and in silico studies were performed to compare A? clearance between mouse and human BBB models. Kinetic studies for A?40 disposition in bEnd3 and hCMEC/D3 cells, representative in vitro mouse and human BBB models, respectively, demonstrated 30-fold higher rate of (125)I-A?40 uptake and 15-fold higher rate of degradation by bEnd3 compared to hCMEC/D3 cells. Expression studies showed both cells to express different levels of P-glycoprotein and RAGE, while LRP1 levels were comparable. Finally, we established a mechanistic model, which could successfully predict cellular levels of (125)I-A?40 and the rate of each process. Established mechanistic model suggested significantly higher rates of A? uptake and degradation in bEnd3 cells as rationale for the observed differences in (125)I-A?40 disposition between mouse and human BBB models. In conclusion, current study demonstrates the important role of BBB in the clearance of A? from the brain. Moreover, it provides insight into the differences between mouse and human BBB with regards to A? clearance and offer, for the first time, a mathematical model that describes A? clearance across BBB. This model is hosted on BioModels Database and identified by: MODEL1409240002. To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

Project description:Alzheimer’s disease (AD) is an unremitting neurodegenerative disorder characterized by cerebral amyloid-β (Aβ) accumulation and gradual decline in cognitive function. Changes in brain energy metabolism arise in the preclinical phase of AD, suggesting an important metabolic component of early AD pathology. Neurons and astrocytes function in close metabolic collaboration, which is essential for the recycling of neurotransmitters in the synapse. However, how this metabolic interplay may be affected during the early stages of AD development has not been sufficiently investigated. Here, we provide an integrative analysis of cellular metabolism during the early stages of Aβ accumulation in the cerebral cortex and hippocampus of the 5xFAD mouse model of AD. Our electrophysiological examination revealed an increase in spontaneous excitatory signaling in hippocampal brain slices of 5xFAD mice. This hyperactive neuronal phenotype coincided with decreased hippocampal TCA cycle metabolism mapped by stable 13C isotope tracing. Particularly, reduced astrocyte TCA cycle activity led to decreased glutamine synthesis, in turn hampering neuronal GABA synthesis in the 5xFAD hippocampus. In contrast, cerebral cortical slices of 5xFAD mice displayed an elevated capacity for oxidative glucose metabolism suggesting a metabolic compensation. When we explored the brain proteome and metabolome of the 5xFAD mice, we found limited changes, supporting that the functional metabolic disturbances between neurons and astrocytes are early events in AD pathology. In addition, we show that synaptic mitochondrial and glycolytic function was impaired selectively in the 5xFAD hippocampus, whereas non-synaptic mitochondrial function was maintained. These findings were supported by ultrastructural analyses demonstrating disruptions in mitochondrial morphology, particularly in the 5xFAD hippocampus. Collectively, our study reveals complex region and cell specific metabolic adaptations, in the early stages of amyloid pathology, which may be fundamental for the progressing synaptic dysfunction in AD.

Dataset Information

Krohn2011 - Cerebral amyloid-β proteostasis regulated by membrane transport protein ABCC1

Publications

Cerebral amyloid-β proteostasis is regulated by the membrane transport protein ABCC1 in mice.

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