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Cerebral Amyloid-Β Proteostasis Is Regulated by the Membrane Transport Protein ABCC1 in Mice

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Cerebral Amyloid-Β Proteostasis Is Regulated by the Membrane Transport Protein ABCC1 in Mice Cerebral amyloid-β proteostasis is regulated by the membrane transport protein ABCC1 in mice Markus Krohn, … , Lary C. Walker, Jens Pahnke J Clin Invest. 2011;121(10):3924-3931. https://doi.org/10.1172/JCI57867. Research Article Neuroscience 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. Find the latest version: https://jci.me/57867/pdf Research article Cerebral amyloid-β proteostasis is regulated by the membrane transport protein ABCC1 in mice Markus Krohn,1,2 Cathleen Lange,1,2 Jacqueline Hofrichter,1,2 Katja Scheffler,1,2 Jan Stenzel,1,2 Johannes Steffen,1 Toni Schumacher,1 Thomas Brüning,1 Anne-Sophie Plath,1,3 Franziska Alfen,1 Anke Schmidt,1,3 Felix Winter,1,2,4 Katja Rateitschak,4 Andreas Wree,5 Jörg Gsponer,6 Lary C. Walker,7 and Jens Pahnke1,2,3 1Department of Neurology, Neurodegeneration Research Laboratory (NRL), 2Interdisciplinary Faculty, Department of Aging Science and Humanities, 3German Centre for Neurodegenerative Diseases (DZNE), Rostock Centre, 4Institute of Systems Biology and Bioinformatics, and 5Institute of Anatomy, University of Rostock, Rostock, Germany. 6Center for High-Throughput Biology, University of British Columbia, British Columbia, Vancouver, Canada. 7Yerkes National Primate Research Center and Department of Neurology, Emory University, Atlanta, Georgia, USA. 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 cere- bral 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 trans- porters could impede the neurodegenerative cascade that culminates in the dementia of AD. Introduction Results Proteostasis is achieved in cells and tissues by interactive mecha- Increased Aβ burden in ABCB1- and ABCC1-deficient mice. We estab- nisms that regulate the production, folding, localization, bind- lished new mouse models that express Swedish mutant human Aβ ing, and disposal of proteins (1). In patients with Alzheimer precursor protein (APPswe) and mutant presenilin-1 (PS1) (here- disease (AD), a disequilibrium of proteostasis in the brain leads after referred to as APP/PS1) that lack specific ABC transporters to the accumulation of oligomeric and fibrillar multimers of — ABCC1 (Abcc1–/–), ABCB1 (Abcb1–/–), and ABCG2 (Abcg2–/–) (see the peptide amyloid-β (Aβ) (1–3). Aβ clearance from the brain Methods). Using Aβ immunohistochemistry, we found highly is reduced by approximately 30% in AD patients compared with significant increases in the cortical load and size of Aβ-positive healthy controls (4). The principal known mechanisms that con- plaques in APP/PS1×Abcc1–/– mice as compared with APP/PS1 tribute to the elimination of Aβ are degradation (by enzymes, mice. APP/PS1×Abcb1–/– mice showed a smaller increase in Aβ the proteasome complex, and autophagy) (5, 6), active, receptor- lesions, but no consistent difference was observed between APP/ mediated transcytotic transport across the blood-brain barrier by PS1 controls and APP/PS1×Abcg2–/– mice (Figure 1 and Supple- LRP1 and RAGE, and by perivascular drainage of the extracellular mental Figure 1, A–D; supplemental material available online with fluid (7–11). In addition, 3 members of the ATP-binding cassette this article; doi:10.1172/JCI57867DS1). Because of variations in transporter family — ABCA1, ABCB1, and ABCG2 — have been the molecular packing density of Aβ in senile plaques, histologi- shown to export Aβ (12–18). Members of different ABC trans- cal assessment of plaques can only yield an approximate estimate porter subfamilies exhibit different export kinetics for specified of the total amount of aggregated Aβ in the brain (21). Thus, we substrates (19, 20). However, the role of the subfamily C of ABC also employed ELISAs for Aβ40 and Aβ42 to determine the total transporters in the export of Aβ has not yet been investigated. To amount of buffer-soluble Aβ (mostly monomers and small oligo- address this question, we compared the ability of specific ABC mers) and guanidine-soluble Aβ (mostly fibrillar material) in the transporters (ABCB1, ABCG2, and ABCC1) to clear Aβ in vitro brain. APP/PS1×Abcc1–/– mice showed a significant increase in and in genetically modified mice. We found that the transporter aggregated (guanidine-soluble) Aβ42 and Aβ40 as compared with ABCC1 strongly influences Aβ transport and accumulation in APP/PS1 control mice at all time points measured (Supplemen- vivo, and thus represents what we believe is a novel target for tal Figure 2A and Supplemental Figure 3A). At 25 weeks of age regulating Aβ proteostasis in the brain. (the oldest age studied), guanidine-soluble Aβ40 and Aβ42 levels were 14-fold and 12-fold greater, respectively, in APP/PS1×Abcc1–/– Authorship note: Markus Krohn and Cathleen Lange contributed equally to this mice than in control mice (Figure 2A, Supplemental Figure 2A, work. and Supplemental Figure 3A). Buffer-soluble Aβ40 and Aβ42 also Conflict of interest: The authors have declared that no conflict of interest exists. increased with age (Supplemental Figure 2B and Supplemental Citation for this article: J Clin Invest. 2011;121(10):3924–3931. doi:10.1172/JCI57867. Figure 3B), but at week 25 (when plaque load was highest), buf- 3924 The Journal of Clinical Investigation http://www.jci.org Volume 121 Number 10 October 2011 research article Figure 1 ABCC1 deficiency promotes Aβ deposition. (A) Cortical areal density of Aβ plaques is elevated by approximately 75% in APP/PS1×Abcc1–/– (controls, black bars; APP/PS1×Abcc1–/–, white bars). (B and C) Mean plaque size is increased (+34%) due to the greater number of plaques (+63%) larger than 700 μm2 and a lower frequency of small plaques (–24%). Error bars show SEM. *P < 0.05. n ≥ 3. (D) Immunohistochemical stains of APP/PS1×Abcg2–/–, APP/PS1×Abcb1–/–, APP/PS1×Abcc1–/–, and control mice reveal the greater areal density of Aβ in Abcc1–/– ani- mals. Typical plaques of similar size are depicted in the insets. Scale bars: 500 μm (insets, 50 μm). Age of animals, 25 weeks. of reduced microglial activity in the augmentation of Aβ pathol- ogy. Double immunostaining for microglia using antibodies to Iba1 and Aβ (23) revealed markedly increased plaque-associated microglia at age 25 weeks in all transporter-deficient strains, with the greatest microgliosis in APP/PS1×Abcc1–/– mice (Supplemental Figure 5), reflecting the increased amyloid burden in these mice and indicating that the exaggerated Aβ burden in this model does not result from a paucity of microglia. ABCC1 facilitates Aβ transport in vitro. To further assess the role of ABCC1 in Aβ clearance, we compared the ability of Abcc1–/– and WT endothelia to transport Aβ42 in vitro in endothelial cell Tran- swell assays (ECTAs) of primary cultured capillary endothelial cells from mouse brains. The deficiency of ABCC1 reduced Aβ42 trans- port by approximately 60% in this in vitro model (Figure 2C). Mathematical simulation and prediction of Aβ clearance kinetics. Next, we wanted to establish whether a single mathematical model that describes the basic physiological processes contrib- uting to the production and removal of Aβ aggregates can cap- ture the kinetics of different Aβ species in the APP/PS1×Abcc1–/– mice. Most importantly, we asked whether such a model would highlight the key role of Aβ transport and whether it would have predictive power for other mouse strains. The model that we developed does not describe detailed mechanisms, but rather fer-soluble Aβ42 levels declined precipitously in the Abcc1–/– group captures the inclusive effect of all essential players in Aβ pro- (Figure 2B). The exaggerated
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