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

Krohn, Markus; Lange, Cathleen; Hofrichter, Jacqueline; Scheffler, Katja; Stenzel, Jan; Steffen, Johannes; Schumacher, Toni; Brüning, Thomas; Plath, Anne-Sophie; Alfen, Franziska; Schmidt, Antje; Winter, Felix; Rateitschak, Katja; Wree, Andreas; Gsponer, Jörg; Walker, Lary C.; Pahnke, Jens

doi:10.1172/jci57867

Cited by 173 publications

(188 citation statements)

References 39 publications

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“…Microglial cells surrounding Aβ-plaques in APP/PS1 mice were found to phagocytose Aβ to a lesser extent than was observed in APP/PS1/Nlrp3 -/-mice. These findings add to evidence suggesting that impaired clearance of Aβ might be a crucial factor in sporadic Alzheimer disease-a view seconded at the meeting by data presented by Jens Pahnke (U. Magdeburg and DZNEMagdeburg, Germany), who showed that loss of ABC transporters B1 and C1, which extrude Aβ from the CNS parenchyma, can lead to a substantial increase in Aβ-load [24]. These transporters not only are regulated by mitochondria [25], but also have a substantial impact on cerebral regeneration [26].…”

Section: Translation Meets Systems Medicinesupporting

confidence: 72%

Between new genetic discoveries and large randomized trials—neurological research in the era of systems medicine

2013

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The 2012 Eibsee meeting on ‘Cellular Mechanisms of Neurodegeneration’ addressed the need to integrate research on classical neurodegenerative mechanisms with investigations that relate to the immunological, glial and vascular sequels that accompany and often propagate neuronal injury. We report on the central topics that were addressed and discuss future directions towards establishing ‘systems neurology’ as a new integrated research field.

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Section: Translation Meets Systems Medicinesupporting

confidence: 72%

Between new genetic discoveries and large randomized trials—neurological research in the era of systems medicine

2013

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“…ATP-binding cassette transporters, as well as being involved in lipid metabolism, cholesterol efflux, and drug transport, are important in removing intracellular Aβ and are dysfunctional in AD; as they are ATP dependent, it has been suggested that reduced energy production could lead to a build-up of Aβ [239]. Specifically, both ABCG2 and ABCC1 have been found to be involved in Aβ transport [240,241]. Whether or not CBD may beneficially act through these transporters is difficult to gauge, as not only might they inhibit ABC-mediated transport of Aβ, but the reported IC 50 may also be too high to be relevant physiologically.…”

Section: Cbd Transporter Targets In Neurodegenerationmentioning

confidence: 99%

Molecular Targets of Cannabidiol in Neurological Disorders

Bih

Chen

Nunn³

et al. 2015

Neurotherapeutics

462

323

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Cannabis has a long history of anecdotal medicinal use and limited licensed medicinal use. Until recently, alleged clinical effects from anecdotal reports and the use of licensed cannabinoid medicines are most likely mediated by tetrahydrocannabinol by virtue of: 1) this cannabinoid being present in the most significant quantities in these preparations; and b) the proportion:potency relationship between tetrahydrocannabinol and other plant cannabinoids derived from cannabis. However, there has recently been considerable interest in the therapeutic potential for the plant cannabinoid, cannabidiol (CBD), in neurological disorders but the current evidence suggests that CBD does not directly interact with the endocannabinoid system except in vitro at supraphysiological concentrations. Thus, as further evidence for CBD's beneficial effects in neurological disease emerges, there remains an urgent need to establish the molecular targets through which it exerts its therapeutic effects. Here, we conducted a systematic search of the extant literature for original articles describing the molecular pharmacology of CBD. We critically appraised the results for the validity of the molecular targets proposed. Thereafter, we considered whether the molecular targets of CBD identified hold therapeutic potential in relevant neurological diseases. The molecular targets identified include numerous classical ion channels, receptors, transporters, and enzymes. Some CBD effects at these targets in in vitro assays only manifest at high concentrations, which may be difficult to achieve in vivo, particularly given CBD's relatively poor bioavailability. Moreover, several targets were asserted through experimental designs that demonstrate only correlation with a given target rather than a causal proof. When the molecular targets of CBD that were physiologically plausible were considered for their potential for exploitation in neurological therapeutics, the results were variable. In some cases, the targets identified had little or no established link to the diseases considered. In others, molecular targets of CBD were entirely consistent with those already actively exploited in relevant, clinically used, neurological treatments. Finally, CBD was found to act upon a number of targets that are linked to neurological therapeutics but that its actions were not consistent withmodulation of such targets that would derive a therapeutically beneficial outcome. Overall, we find that while >65 discrete molecular targets have been reported in the literature for CBD, a relatively limited number represent plausible targets for the drug's action in neurological disorders when judged by the criteria we set. We conclude that CBD is very unlikely to exert effects in neurological diseases through modulation of the endocannabinoid system. Moreover, a number of other molecular targets of CBD reported in the literature are unlikely to be of relevance owing to effects only being observed at supraphysiological concentrations. Of interest and after excludin...

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“…The decline of the levels of the transporter at the BBB occurs during normal aging, and is positively correlated with the accumulation of Aβ (Silverberg et al, 2010). Due the contribution of ABC transporters on Aβ clearance in AD, they have been proposed as potential therapeutic targets (Krohn et al, 2011). Moreover, ABCB1 dysfunction has been also associated with other neurodegenerative disorders such as PD, progressive supranuclear palsy (PSP) or genetically associated with depressive disorders (Bernstein et al, 2014).…”

Section: Abc Transportersmentioning

confidence: 99%

Nrf2 activation in the treatment of neurodegenerative diseases: a focus on its role in mitochondrial bioenergetics and function

Esteras¹,

Dinkova‐Kostova²,

Abramov³

2016

Biological Chemistry

143

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Abstract:The nuclear factor erythroid-derived 2 (NF-E2)-related factor 2 (Nrf2) is a transcription factor wellknown for its function in controlling the basal and inducible expression of a variety of antioxidant and detoxifying enzymes. As part of its cytoprotective activity, increasing evidence supports its role in metabolism and mitochondrial bioenergetics and function. Neurodegenerative diseases are excellent candidates for Nrf2-targeted treatments. Most neurodegenerative conditions such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, frontotemporal dementia and Friedreich's ataxia are characterized by oxidative stress, misfolded protein aggregates, and chronic inflammation, the common targets of Nrf2 therapeutic strategies. Together with them, mitochondrial dysfunction is implicated in the pathogenesis of most neurodegenerative disorders. The recently recognized ability of Nrf2 to regulate intermediary metabolism and mitochondrial function makes Nrf2 activation an attractive and comprehensive strategy for the treatment of neurodegenerative disorders. This review aims to focus on the potential therapeutic role of Nrf2 activation in neurodegeneration, with special emphasis on mitochondrial bioenergetics and function, metabolism and the role of transporters, all of which collectively contribute to the cytoprotective activity of this transcription factor.

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

Cited by 173 publications

References 39 publications

Between new genetic discoveries and large randomized trials—neurological research in the era of systems medicine

Between new genetic discoveries and large randomized trials—neurological research in the era of systems medicine

Molecular Targets of Cannabidiol in Neurological Disorders

Nrf2 activation in the treatment of neurodegenerative diseases: a focus on its role in mitochondrial bioenergetics and function

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