308 Fig. 11 Vascular smooth muscle cells are degenerated and severely affected in CAA- laden cerebral vessels in late- stage TG arcAb mice. CAA- laden arteries and arterioles in late-stage TG arcAb mice showed a characteristic thickening of the laminin basement membrane (a, upper arrows) and dust-like laminin particles were regularly observed (a, lower arrow). Vascular SMC layers were severely degenerated or completely absent (a, asterisk and arrows; c). In contrast, NTG littermates were found to have a typical laminin basement membrane thickness (b) and an intact, uninterrupted vascular SMC stratum (b, arrow and asterisk). Plus signs in a show presence of mouse IgG which was detected by the same secondary anti-mouse antibody (FITC-tagged donkey anti- mouse IgG) used to visualise primary anti-smooth muscle actin antibody which was raised in mouse, explaining the presence of both smooth muscle cell and endogenous mouse IgG on the same brain sections. Scale bar a 150 lm Acta Neuropathol (2011) 122:293–311 retraction and swelling [2, 63]. It is well established that CNS entry of components of the peripheral immune system is part of the AD pathology [13]. Taking into account our ﬁndings on the pathological cerebral extravasation of the BBB viability marker Trypan Blue and vessel wall insta- bility as shown by leakage of vascular casting resin in the TG arcAb mice, a role for components of the peripheral immune system in (further) triggering pathological astro- cyte responses including endfeet retraction could indeed be possible [1, 13, 65]. It is clear that with astrocyte endfeet abnormalities already present at the early-stage pathology, impaired BBB functioning is a premature process in the arcAb mouse. An astrocytic involvement at premature time points in the pathology was further indicated by astrogli- osis with paralleled increase in vascular laminin and astrocytic laminin secretion ex vivo in the early-stage mice. Increase in laminin VBM in these relatively young mice with little Ab plaque burden seems to be contradictory with the unique CAA-related increase in laminin we found in mid-stage and late-stage mice. It is interesting, however, that mainly the incoming arteries from leptomeningeal 123 origin showed this increased astrocyte activation in the early-stage TG mice with concomitant increase in VBM laminin. It is exactly these vessels which are the ﬁrst to be affected by CAA at later disease stages in the arcAb mouse and other transgenic AD mouse models [58, 59]. The induction of signal transduction cascades within the endothelium can trigger astrocytic release of endothelium- protective molecules [1]. This protective reaction could be elicited by soluble Ab species which are known to induce astrocyte activation and to be toxic to endothelial cells and SMCs [18, 51, 56, 60]. Furthermore, laminin expression is known to be up-regulated by damage to the vasculature [4, 65]. Soluble Ab species mainly as toxic protoﬁbrils are abundantly present in arcAb mice from 2 months of age onwards [31, 35] and could be directed to the vasculature by the forces of the cerebrovascular drainage pathways in which especially the cerebral arteries are involved [9, 20, 58], providing a possible explanation for the unique loca- tion of these reactive astrocytes around blood vessels. Seen in this light, laminin is known to interact with Ab, inhib- iting its ﬁbrillisation and diluting its neurotoxicity [27, 36],