Acta Neuropathol (2011) 122:293–311 DOI 10.1007/s00401-011-0834-y O R I G I N A L P A P E R Vascular b-amyloid and early astrocyte alterations impair cerebrovascular function and cerebral metabolism in transgenic arcAb mice Mario Merlini • Eric P. Meyer • Alexandra Ulmann-Schuler • Roger M. Nitsch Received: 10 December 2010 / Revised: 11 April 2011 / Accepted: 4 May 2011 / Published online: 19 June 2011 The Author(s) 2011. This article is published with open access at Springerlink.com Abstract Cerebrovascular lesions related to congophilic amyloid angiopathy (CAA) often accompany deposition of b-amyloid (Ab) in Alzheimer’s disease (AD), leading to disturbed cerebral blood ﬂow and cognitive dysfunction, posing the question how cerebrovascular pathology con- tributes to the pathology of AD. To address this question, we characterised the morphology, biochemistry and func- tionality of brain blood vessels in transgenic arctic b-amyloid (arcAb) mice expressing human amyloid pre- cursor protein (APP) with both the familial AD-causing Swedish and Arctic mutations; these mice are characterised by strong CAA pathology. Mice were analysed at early, mid and late-stage pathology. Expression of the glucose transporter GLUT1 at the blood–brain barrier (BBB) was signiﬁcantly decreased and paralleled by impaired in vivo blood-to-brain glucose transport and reduced cerebral lac- tate release during neuronal activation from mid-stage pathology onwards. Reductions in astrocytic GLUT1 and lactate transporters, as well as retraction of astrocyte end- feet and swelling consistent with neurovascular uncoupling, preceded wide-spread b-amyloid plaque pathology. We M. Merlini (&) R. M. Nitsch (&) Division of Psychiatry Research, University of Zu¨rich, August Forel-Strasse 1, 8008 Zurich, Switzerland e-mail: mario.merlini@gladstone.ucsf.edu R. M. Nitsch e-mail: nitsch@bli.uzh.ch E. P. Meyer A. Ulmann-Schuler Institute of Molecular Life Sciences, University of Zu¨rich, Winterthurerstrasse 190, 8057 Zurich, Switzerland Present Address: M. Merlini Gladstone Institute of Neurological Disease, 1650 Owens Street, San Francisco, CA 94158, USA show that CAA at later disease stages is accompanied by severe morphological alterations of brain blood vessels including stenoses, BBB leakages and the loss of vascular smooth muscle cells (SMCs). Together, our data establish that cerebrovascular and astrocytic pathology are paralleled by impaired cerebral metabolism in arcAb mice, and that astrocyte alterations occur already at premature stages of pathology, suggesting that astrocyte dysfunction can con- tribute to early behavioural and cognitive impairments seen in these mice. Keywords Alzheimer’s disease Congophilic amyloid angiopathy Cerebral glucose metabolism Astrocytes Introduction Vascular accumulation of b-amyloid (Ab) results in con- gophilic amyloid angiopathy (CAA), a vascular lesion diagnosed as part of b-amyloid pathology in up to 90% of post-mortem brains with a neuropathological diagnosis of Alzheimer’s disease (AD) [57]. CAA is associated with a plethora of abnormalities and malfunctioning of the cere- brovasculature [6, 15, 40, 49, 52, 64] including ruptures of the vessel walls causing microhaemorrhages and lesions of the blood–brain barrier (BBB), resulting in inﬂammation, vascular oedema and uncontrolled inﬂux of peripheral blood components into the brain parenchyma [65]. As a result of CAA, vascular basement membranes (VBM) thicken and smooth muscle cells (SMC) degenerate, jointly leading to impaired cerebral blood ﬂow (CBF) [15, 18, 40]. Physiological functions of the cerebral vasculature are compromised early, possibly even preceding the onset of AD pathology including the onset of CAA, and raising the 123