Acta Neuropathol (2011) 122:293–311 307 Fig. 10 Vascular basement membrane abnormalities in mid and late- stage TG arcAb mice. Constrictions/stenoses (a, plus signs) and localised thickening of the vessel walls (a, asterisks) were abundantly seen on CAA-laden vessels in brains of late-stage TG arcAb mice. These basement membrane irregularities due to laminin over-expres- sion (a) were conﬁned to those parts of the cerebral vessels that were affected by CAA; all other parts showed normal laminin expression and smooth vessel wall appearance (a, arrows). Severe CAA in late- stage TG arcAb mice (b) caused both intense and signiﬁcant increase We detected signs of neurovascular uncoupling represented by astrocyte endfeet retraction and swelling, possibly also (partly) explaining our ﬁndings on impaired metabolism. We observed this starting at an early pathological stage of the disease, at which extracellular Ab plaque burden is small in the arcAb mouse. Only astrocytes surrounding diffuse Ab plaques and vascular Ab deposits showed endfeet abnormalities even at the late-stage pathology, suggesting that Ab instigates the loss of neurovascular coupling rather than the process of ageing or the mere presence of the APP transgene in these mice. The mecha- nism by which Ab prevents contact between endfeet could be the formation of a physical barrier between blood ves- sels and astrocytes. Another likely mechanism underlying this impaired astrocyte-endothelium interaction could be the loss of expression of the astrocyte endfeet—VBM linker b dystroglycan as we observed in our TG arcAb in laminin immunopositivity and rupture of the vascular basement membrane laminin (b, arrow; c and d). In addition, dust-like laminin particles could be observed surrounding the affected vessel (b, asterisk). Cerebral vessels of arcAb NTG littermates lacked CAA and vascular basement membranes showed typical laminin immunoposi- tivity (b, last two image sets). Scale bar a 150 lm; b 30 lm. Hue settings of ﬂuorescence for Ab were altered for more contrast effect explaining the blue colour mice [2, 53]. It is unclear whether Ab toxicity is involved in the attenuated b dystroglycan expression or that the changes in the VBM we describe here and were described by others [21] are culprit. Interestingly, however, the degree of b dystroglycan loss was paralleled by the pres- ence of diffuse, parenchymal Ab plaques and leakage of endogenous IgG into the brain. Astrocyte endfeet form an essential part of the BBB [1] and the question is if detachment of astrocyte endfeet from the vasculature leading to disruption of the BBB and hence extravasation of serum proteins into the CNS or that entry of serum proteins into the brain is responsible for this aspect of neurovascular uncoupling. Brains of multiple sclerosis patients and its in vivo counterpart experimental autoim- mune encephalomyelitis show that neuroinﬂammation and extravasation of components of the peripheral immune system induce astrocyte endfeet abnormalities including 123