PREFACE: Alzheimer’s disease is one of the most devastating diseases of the elderly, and is predicted to afflict over 100 million patients worldwide by the year 2050. Although some cases of Alzheimer’s disease are caused by rare genetic mutations, the vast majority (99%) - so-called sporadic Alzheimer’s disease - have no known cause. Furthermore, despite intense research efforts in the past two decades, no treatment is yet available that significantly slows the course of the disease. Because Alzheimer’s disease involves the abnormal accumulation of specific proteins in the brain, and because the mechanisms of protein disposal decline in old age, recent research has sought to determine how to promote the removal of these abnormal proteins from the aging brain. One focus of this research has been the cerebral blood vessels. The brain is protected by the blood-brain barrier, a complex assortment of obstacles and selective molecular transporters that tightly regulate the passage of materials to and from the brain. Growing evidence indicates that the transporters of the blood-brain barrier can be exploited to accelerate the removal of a toxic protein fragment called β-amyloid, which aggregates to form senile plaques and other lesions in Alzheimer’s disease.
RECENT DISCOVERY: Over the past seven years, Jens Pahnke and his team from the University of Rostock and the German Center for Neurodegenerative Diseases (DZNE, founded 2 years ago) established a collection of new Alzheimer’s disease mouse models with deficiencies in specific transport molecules in the brain’s blood vessels. Analysis of these models, in collaboration with colleagues from the US (Emory University) and Canada (University of British Columbia) revealed that a molecular transporter called ABCC1 is a potent exporter of the toxic amyloid from the brain. Previous studies had shown that a related transporter (ABCB1) also slightly regulates amyloid levels, but the current study, by comparing amyloid levels in mice lacking different transporters, found that ABCC1 transporter-deficiency alone caused a vast 12-fold increase in the levels of amyloid in the brain. These new discoveries were confirmed in cell assays and in additional mouse models with a type of amyloidosis that selectively affected the brain’s blood vessels. The role of ABCC1 in regulating brain amyloid levels was then assessed in a comprehensive mathematical model of amyloid kinetics to predict disease onset and course.
To determine the translational potential of these findings, Pahnke and colleagues then searched for drugs that activate ABCC1. Previously, the pharmaceutical industry has focused mainly on the inactivation of ABC transporters because they contribute to the resistance of cancers to chemotherapeutic drugs. However, thiethylperazine (Torecan®) is an ABCC1-activator that is approved by the FDA for the treatment of vomiting and nausea. The German group found that thiethylperazine reduces brain amyloid levels in transgenic mouse models by up to 70% within 25 days.
RELEVANCE: This study provides the first evidence for an important new mechanism in that the ABCC1 transporter strongly regulates the levels of the pathogenic Alzheimer’s protein in the brains of mouse models. In addition to identifying a potential new therapeutic target, this discovery could also account for the variation in the age of onset and clinical course of sporadic Alzheimer’s disease cases. In particular, the ABC transporters are highly regulated by mitochondria, the cell’s power plants, which undergo substantial decline with advancing age.
This newly recognized molecular clearance mechanism suggests a novel approach to the treatment or prevention of Alzheimer’s disease.
REFERENCE: M Krohn*, C Lange*, J Hofrichter, K Scheffler, J Stenzel, J Steffen, T Schumacher, T Brüning, AS Plath, F Alfen, A Schmidt, F Winter, K Rateitschak, A Wree, J Gsponer, LC Walker, and J Pahnke: Cerebral amyloid-β proteostasis is highly regulated by the membrane transport protein ABCC1 in mice, published in: The Journal of Clinical Investigation, 01.09.2011 New online first (http://www.jci.org/just-published)
CONTACT INFORMATION:
Prof Jens Pahnke, MD PhD EFN,
University of Rostock,
E-Mail: jens.pahnke@uni-rostock.de,
Tel: +49 381 494 4700,
Web: www.NRL.uni-rostock.de
Press office of the University of Rostock:
Dr Ulrich Vetter,
E-mail: ulrich.vetter@uni-rostock.de,
Tel: +49 381 498 1013,
Web: www.uni-rostock.de