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Brain Advance Access published online on July 16, 2007
Brain, doi:10.1093/brain/awm156
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© 2007 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Age-dependent cerebrovascular dysfunction in a transgenic mouse model of cerebral amyloid angiopathy

Hwa Kyoung Shin1, Phillip B. Jones2, Monica Garcia-Alloza2, Laura Borrelli2, Steven M. Greenberg3, Brian J. Bacskai2, Matthew P. Frosch2, Bradley T. Hyman2, Michael A. Moskowitz1 and Cenk Ayata1,3

1Stroke and Neurovascular Regulation Laboratory, Department of Radiology, 2Alzheimer's Disease Research Laboratory and 3Stroke Service and Neuroscience Intensive Care Unit, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA

Correspondence to: Cenk Ayata, MD, Stroke and Neurovascular Regulation Laboratory, 149 13th Street, Room 6403, Charlestown, MA 02129, USA E-mail: cayata{at}partners.org

The Tg2576 transgenic mouse model of human cerebral amyloid angiopathy is characterized by age-dependent cerebrovascular deposition of amyloid-ß (Aß) starting from 9 months of age and progressively worsening to involve most pial arterioles by 18 months; soluble Aß levels are elevated long before vascular deposition takes place in this model. It has been suggested that elevated soluble Aß levels alone are sufficient to impair cerebral blood flow (CBF) regulation thereby contributing to the early progression of Alzheimer's disease. Using laser speckle flowmetry through an intact skull, we studied the impact of elevated soluble Aß levels and vascular Aß deposition on a wide range of CBF responses to evaluate vasodilation and vasoconstriction in young or aged Tg2576 mice. Nineteen-month-old Tg2576 with severe vascular Aß deposits showed an attenuated hyperaemic response during hypercapnia and whisker stimulation compared to wild-type littermates. The anticipated increase in CBF due to isoflurane anaesthesia was also suppressed, as were the typical hypoperfusion responses during cortical spreading depression and {alpha}-chloralose anaesthesia. The responses of 8-month-old Tg2576 with elevated soluble Aß levels, but without vascular Aß deposition, did not differ from age-matched controls. In conclusion, our data suggest that vascular Aß deposition is associated with impaired vasodilator as well as vasoconstrictor responses to a wide range of stimuli. These responses do not differ from controls when studied non-invasively prior to vascular Aß deposition, thus challenging the view that elevated soluble Aß levels are sufficient to cause cerebrovascular dysfunction.

Key Words: cerebral blood flow; laser speckle flowmetry; hypercapnia; whisker stimulation; spreading depression

Abbreviations: CAA, cerebral amyloid angiopathy; CSD, cortical spreading depression; LSF, laser speckle flowmetry

Received January 17, 2007. Revised May 25, 2007. Accepted June 13, 2007.


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