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Vascular β-amyloid and early astrocyte alterations impair cerebrovascular function and cerebral metabolism in transgenic arcAβ mice.
Acta Neuropathol. 2011 Sep; 122(3):293-311.AN

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+Show Affiliations

Division of Psychiatry Research, University of Zürich, August Forel-Strasse 1, 8008, Zurich, Switzerland. mario.merlini@gladstone.ucsf.eduNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

21688176

Citation

Merlini, Mario, et al. "Vascular Β-amyloid and Early Astrocyte Alterations Impair Cerebrovascular Function and Cerebral Metabolism in Transgenic arcAβ Mice." Acta Neuropathologica, vol. 122, no. 3, 2011, pp. 293-311.
Merlini M, Meyer EP, Ulmann-Schuler A, et al. Vascular β-amyloid and early astrocyte alterations impair cerebrovascular function and cerebral metabolism in transgenic arcAβ mice. Acta Neuropathol. 2011;122(3):293-311.
Merlini, M., Meyer, E. P., Ulmann-Schuler, A., & Nitsch, R. M. (2011). Vascular β-amyloid and early astrocyte alterations impair cerebrovascular function and cerebral metabolism in transgenic arcAβ mice. Acta Neuropathologica, 122(3), 293-311. https://doi.org/10.1007/s00401-011-0834-y
Merlini M, et al. Vascular Β-amyloid and Early Astrocyte Alterations Impair Cerebrovascular Function and Cerebral Metabolism in Transgenic arcAβ Mice. Acta Neuropathol. 2011;122(3):293-311. PubMed PMID: 21688176.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Vascular β-amyloid and early astrocyte alterations impair cerebrovascular function and cerebral metabolism in transgenic arcAβ mice. AU - Merlini,Mario, AU - Meyer,Eric P, AU - Ulmann-Schuler,Alexandra, AU - Nitsch,Roger M, Y1 - 2011/06/19/ PY - 2010/12/10/received PY - 2011/05/04/accepted PY - 2011/04/11/revised PY - 2011/6/21/entrez PY - 2011/6/21/pubmed PY - 2012/1/11/medline SP - 293 EP - 311 JF - Acta neuropathologica JO - Acta Neuropathol. VL - 122 IS - 3 N2 - 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. SN - 1432-0533 UR - https://www.unboundmedicine.com/medline/citation/21688176/Vascular_β_amyloid_and_early_astrocyte_alterations_impair_cerebrovascular_function_and_cerebral_metabolism_in_transgenic_arcAβ_mice_ L2 - https://dx.doi.org/10.1007/s00401-011-0834-y DB - PRIME DP - Unbound Medicine ER -