304 Acta Neuropathol (2011) 122:293–311 Fig. 7 Morphological alterations of the cerebrovasculature in late- stage TG arcAb mice. Scanning electron microscopy (SEM) of late- stage arcAb NTG littermates showed clear and regular endothelial cell imprints on arterial vessel walls (a, arrow) and a smooth appearance of the vessel wall. In contrast, late-stage TG arcAb mice presented a tree bark-like vessel wall and degenerated, often absent endothelial cell imprints (b, arrow). Furthermore, extensive stenoses and bulging of the vessel wall were observed both on arteries and arterioles (b, asterisks and inset). Ball-shaped leakages of the perfusion resin were found on arteries, arterioles and capillaries of the TG arcAb mice (c, arrows). Loose vessel ends were observed as well (c, asterisk). Whereas the NTG littermates showed a dense and constant vascular bed, the density of the vascular bed in the TG animals was reduced showing numerous gaps, especially in the area of the temporal lobe (d, arrows). Scale bar a 100 lm; b and c 50 lm; d 1 mm were co-localised with CAA present on the vessels (Fig. 10a). Those parts of the same vessels without CAA appeared to be normal and showed no increase in lam- inin immunoreactivity (Fig. 10a, arrows), indicating a relationship between CAA and the morphological alter- ations seen in the SEM analyses (Fig. 7). Severe CAA as uniquely observed in late-stage TG arcAb mice (Fig. 10b) caused not only such strong laminin up-reg- ulation in the VBM but lead to rupture of the vessel wall as well (Fig. 10b, arrow). In addition, dust-like laminin particles surrounding the ruptured vessels were abun- dantly observed (Fig. 10b, asterisk). NTG littermates presented typical laminin immunoreactivity of the VBM (Fig. 10b). Congophilic amyloid angiopathy strongly and signiﬁ- cantly affected the expression of vascular SMCs in late- stage TG animals with SMC loss paralleled by interrup- tions in SMC strata (Fig. 11a, arrows and Fig. 11c). In contrast, non-CAA-affected vessels presented intact, uninterrupted vascular SMC layers similar to vessels of their NTG littermates (Fig. 11b). 123 Discussion Vascular pathology is a critical and more and more recognised component of AD, impairing blood-to-brain inﬂux of nutrients essential for cerebral functioning and brain-to-blood efﬂux of cerebral waste products leading to cognitive deterioration [10, 11, 64, 65]. By characterising the transgenic arcAb mouse model of AD—which presents a strong vascular pathology—at early, mid and late disease stages we investigated what processes could possibly instigate the vascular and metabolic impairments early on in the disease and which mechanisms aggravate the vas- cular pathology at later stages in this AD mouse model. Decreased endothelial GLUT1 expression has been found in transgenic mouse models of AD and in human AD patients [15, 22, 26, 47]. We observed lowered GLUT1 protein expression in TG animals starting at mid-stage disease pathology when CAA formation is apparent in these mice and diffuse Ab plaques are becoming wide- spread. As GLUT1 is the sole glucose transporter expres- sed by brain endothelial cells and peripheral supply is the