Research Report Apolipoprotein E protects cultured pericytes and astrocytes from D-Aβ 1–40 -mediated cell death Ilona B. Bruinsma a,b, ⁎ , Micha M.M. Wilhelmus a,c,e , Matthijs Kox c , Robert Veerhuis d , Robert M.W. de Waal c , Marcel M. Verbeek a,b a Radboud University Nijmegen Medical Centre, Donders Institute for Brain, Cognition and Behaviour, Centre for Neuroscience, Department of Neurology and Alzheimer Centre, Nijmegen, The Netherlands b Radboud University Nijmegen Medical Centre, Department of Laboratory Medicine, Nijmegen, The Netherlands c Radboud University Nijmegen Medical Centre, Donders Institute for Brain, Cognition and Behaviour, Centre for Neuroscience, Department of Pathology, Nijmegen, The Netherlands d Departments of Pathology, Psychiatry, Clinical Chemistry and Alzheimer Centre, VU University Medical Center, Amsterdam, The Netherlands e Department of Anatomy and Neurosciences, VU University Medical Center, Amsterdam, The Netherlands ARTICLE INFO ABSTRACT Article history: Accepted 12 December 2009 Available online 23 December 2009 Cerebral amyloid angiopathy (CAA) is a common pathological finding in Alzheimer's disease and hereditary cerebral hemorrhage with amyloidosis of the Dutch type; in this latter condition it is caused by deposition of mutated amyloid β protein (Aβ Glu22Gln; D-Aβ 1–40 ). Previously, we found a dependence of the Aβ-mediated toxicity and apolipoprotein E (apoE) production by cultured pericytes on apoE genotype. Given their close association with the cerebrovascular wall both astrocytes and pericytes may be involved in CAA development, a process that includes Aβ deposition and clearance and that may be affected by interaction with locally produced apolipoprotein E (apoE). Although astrocytes are regarded as the major source of apolipoprotein E (apoE) in the brain, also pericytes produce apoE. In this study we compared the apoE production capacity, the effects of apoE on D-Aβ 1–40 internalization, D-Aβ 1–40 cell surface accumulation and the vulnerability for D-Aβ 1–40 - induced toxicity of either cell type in order to quantify the relative contributions of astrocytes and pericytes in the various processes that contribute to CAA formation. Strikingly, cultured astrocytes produced only 3–10% of the apoE amounts produced by pericytes. Furthermore, pericytes with the apoE ɛ4 allele produced three times less apoE and were more vulnerable to D-Aβ 1–40 treatment than pericytes without an ɛ4 allele. Such relations were not observed with astrocytes in vitro. Both pericytes and astrocytes, however, were protected from Aβ-induced cytotoxicity by high levels of pericyte-derived apoE, but not recombinant apoE. In addition, pericyte-derived apoE dose-dependently decreased both internalization of Aβ and Aβ accumulation at the cell surface in either cell type. The present data suggest that apoE produced by pericytes, rather than astrocyte-produced apoE, Keywords: Amyloid-β with Dutch mutation Apolipoprotein E Internalization Accumulation Cytotoxicity BRAIN RESEARCH 1315 (2010) 169 – 180 ⁎ Corresponding author. Department of Neurology, 830 LGEM, Radboud University Nijmegen Medical Centre, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands. Fax: +31 243668754. E-mail address: i.bruinsma@neuro.umcn.nl (I.B. Bruinsma). Abbreviations: HBPs, human brain pericytes; SMCs, smooth muscle cells; D-Aβ 1-40 , amyloid beta (1–40) with the Dutch mutation; AD, Alzheimer's disease; CAA, cerebral amyloid angiopathy; SPs, senile plaques; HCHWA-D, hereditary cerebral hemorrhage with amyloidosis of the Dutch type 0006-8993/$ – see front matter © 2009 Elsevier B.V. All rights reserved. doi:10.1016/j.brainres.2009.12.039 available at www.sciencedirect.com www.elsevier.com/locate/brainres