Acta Neuropathol (2011) 122:293–311 giving foundation to the idea that astrocytic laminin release as we detected could be a protective mechanism to both strengthen the vessel wall by increasing VBM thickness and an attempt to reduce Ab-induced neuro- and vascular toxicity by interfering with (further) Ab ﬁbrillisation. Although we found astrocytes to secrete laminin as was observed by others as well [8, 45], it cannot be excluded that endothelial cells themselves are involved too as these cells can secrete laminin [19]. Although possibly being an astrocytic protection attempt, an increase in laminin secretion paralleled by VBM thickening leads to vessel wall rigidity and hence reduced CBF, especially the lep- tomeningeal vessel wall thickening we observed in early- stage TG arcAb mice which directly affects downstream perfusion of the arterioles and capillaries [23, 30]. Cerebral hypoperfusion—and with that reduced oxygen and glucose supply and hindered cerebral drainage of cerebral waste products—starting at such early age could be at the base of the accumulation of Ab and the severe CAA-related vas- cular pathology with vascular SMC loss and BBB impairments as we observed later on at mid- and late-stage pathology in the arcAb mice. Together, our data underscore the role of the impaired brain vascular system accompanying b-amyloid pathology [4, 7, 17, 59, 64] and they establish that astrocytes are already involved early on in the disease in arcAb mice, with further age-related progression in severity. Further, our data suggest that impaired functions of astrocytes related to cerebral energy deﬁcits may contribute to decreased neuronal and vascular functions followed later by pathological stages of b-amyloid pathology in arcAb mice. Acknowledgments We thank Drs. Antonella Chadha-Santuccione and Zoe¨ Goodger for careful reading of the manuscript and Daniel Schuppli for breeding and caretaking of the arcAb mice. This work was funded by the Swiss National Science Foundation SNSF, grant number 3200B0-112616/1, and the National Centre of Competence in Research NCCR ‘‘Neural Plasticity and Repair’’, project 2. Conﬂict of interest The authors declare that they have no conﬂict of interest. Open Access This article is distributed under the terms of the Creative Commons Attribution Noncommercial License which per- mits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited. References 1. Abbott NJ, Ro¨nnba¨ck L, Hansson E (2006) Astrocyte-endothelial interactions at the blood–brain barrier. Nat Rev Neurosci 7:41–53 2. 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