title: Vascular β-amyloid and early astrocyte alterations impair cerebrovascular function and cerebral metabolism in transgenic arcAβ mice.
abstract: Cerebrovascular lesions related to congophilic amyloid angiopathy (CAA) often accompany deposition of β-amyloid (Aβ) in Alzheimer's disease (AD), leading to disturbed cerebral blood flow and cognitive dysfunction, posing the question how cerebrovascular pathology contributes to the pathology of AD. To address this question, we characterised the morphology, biochemistry and functionality of brain blood vessels in transgenic arctic β-amyloid (arcAβ) mice expressing human amyloid precursor 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 lactate release during neuronal activation from mid-stage pathology onwards. Reductions in astrocytic GLUT1 and lactate transporters, as well as retraction of astrocyte endfeet and swelling consistent with neurovascular uncoupling, preceded wide-spread β-amyloid plaque pathology. We 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 arcAβ mice, and that astrocyte alterations occur already at premature stages of pathology, suggesting that astrocyte dysfunction can contribute to early behavioural and cognitive impairments seen in these mice.
authors.affiliation: Division of Psychiatry Research, University of Zürich, August Forel-Strasse 1, 8008, Zurich, Switzerland. mario.merlini@gladstone.ucsf.edu
authors.forename: Mario
authors.initials: M
authors.lastname: Merlini
authors.forename: Eric P
authors.initials: EP
authors.lastname: Meyer
authors.forename: Alexandra
authors.initials: A
authors.lastname: Ulmann-Schuler
authors.forename: Roger M
authors.initials: RM
authors.lastname: Nitsch
mesh_terms: D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology* / Q000648:ultrastructure; D001485:Basement Membrane / Q000378:metabolism / Q000473:pathology; D001812:Blood-Brain Barrier / Q000473:pathology / Q000503:physiopathology; D001921:Brain / Q000473:pathology; D018929:Cell Culture Techniques; D016657:Cerebral Amyloid Angiopathy / Q000150:complications* / Q000235:genetics / Q000473:pathology; D002536:Cerebral Arteries / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D002561:Cerebrovascular Disorders / Q000209:etiology* / Q000473:pathology*; D004195:Disease Models, Animal; D018450:Disease Progression; D049030:Dystroglycans / Q000378:metabolism; D004727:Endothelium / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation / Q000235:genetics; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D051272:Glucose Transporter Type 1 / Q000235:genetics / Q000378:metabolism; D006470:Hemorrhage / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D006801:Humans; D043322:Lactase / Q000378:metabolism; D007797:Laminin / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D017551:Microdialysis / Q000379:methods; D008855:Microscopy, Electron, Scanning / Q000379:methods; D027501:Monocarboxylic Acid Transporters / Q000235:genetics / Q000378:metabolism; D009130:Muscle, Smooth / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D058225:Plaque, Amyloid / Q000378:metabolism / Q000473:pathology; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D027981:Symporters / Q000235:genetics / Q000378:metabolism; D000099233:Monocarboxylate Transport Protein 1
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D049030:Dystroglycans; D005904:Glial Fibrillary Acidic Protein; D005947:Glucose; D051272:Glucose Transporter Type 1; D043322:Lactase; D007797:Laminin; D027501:Monocarboxylic Acid Transporters; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D027981:Symporters; D000099233:Monocarboxylate Transport Protein 1