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Amyloid-?-dependent compromise of microvascular structure and function in a model of Alzheimer’s disease

Amyloid-?-dependent compromise of microvascular structure and function in a model of Alzheimer’s disease
Amyloid-?-dependent compromise of microvascular structure and function in a model of Alzheimer’s disease
The majority of patients with Alzheimer's disease have cerebral amyloid angiopathy, thus showing deposition of amyloid-? peptides in the walls of leptomeningeal and cortical arterioles. These deposits are believed to result from impaired clearance of parenchymal amyloid-? peptides. In the current work, we examined the changes in cortical microvascular structure and function in situ in TgCRND8, a transgenic mouse model of Alzheimer's disease. In contrast to venules, cortical arterioles were shown to increase in tortuosity and decrease in calibre with amyloid-? peptide accumulation. These structural changes were accompanied by progressive functional compromise, reflected in higher dispersion of microvascular network transit times, elongation of the transit times, and impaired microvascular reactivity to hypercapnia in the transgenic mice. Moreover, inhibition of amyloid-? peptide oligomerization and fibrillization via post-weaning administration of scyllo-inositol, a naturally occurring stereoisomer of myo-inositol, rescued both structural and functional impairment of the cortical microvasculature in this Alzheimer's disease model. These results demonstrate that microvascular impairment is directly correlated with amyloid-? accumulation and highlight the importance of targeting cerebrovascular amyloid angiopathy clearance for effective diagnosis, monitoring of disease progression and treatment of Alzheimer's disease.
cerebral amyloid angiopathy, vessel tortuosity, microvasculature, two-photon fluorescence microscopy, scyllo-inositol
0006-8950
3039-3050
Dorr, A.
12479cb3-5a4c-42f1-be1f-32822aa77f09
Sahota, B.
51a96557-c24d-4723-a724-287f9388a362
Chinta, L.V.
27cb3127-241b-4972-8619-49340ea781e8
Brown, M.E.
4f061b1c-b71a-485f-9bb7-d8262550daca
Lai, A.Y.
b75ef846-cc3a-4083-9e86-d04b3ddbafa3
Ma, K.
71827cc4-e5ec-4876-8e2c-06a5e2194372
Hawkes, C.A.
88f4a99a-625c-4c6e-a295-09dd67f8afe8
McLaurin, J.
196bc965-5bf0-4168-8963-15afe2170798
Stefanovic, B.
633a31af-da26-4379-af36-354383e702e3
Dorr, A.
12479cb3-5a4c-42f1-be1f-32822aa77f09
Sahota, B.
51a96557-c24d-4723-a724-287f9388a362
Chinta, L.V.
27cb3127-241b-4972-8619-49340ea781e8
Brown, M.E.
4f061b1c-b71a-485f-9bb7-d8262550daca
Lai, A.Y.
b75ef846-cc3a-4083-9e86-d04b3ddbafa3
Ma, K.
71827cc4-e5ec-4876-8e2c-06a5e2194372
Hawkes, C.A.
88f4a99a-625c-4c6e-a295-09dd67f8afe8
McLaurin, J.
196bc965-5bf0-4168-8963-15afe2170798
Stefanovic, B.
633a31af-da26-4379-af36-354383e702e3

Dorr, A., Sahota, B., Chinta, L.V., Brown, M.E., Lai, A.Y., Ma, K., Hawkes, C.A., McLaurin, J. and Stefanovic, B. (2012) Amyloid-?-dependent compromise of microvascular structure and function in a model of Alzheimer’s disease. Brain, 135 (10), 3039-3050. (doi:10.1093/brain/aws243).

Record type: Article

Abstract

The majority of patients with Alzheimer's disease have cerebral amyloid angiopathy, thus showing deposition of amyloid-? peptides in the walls of leptomeningeal and cortical arterioles. These deposits are believed to result from impaired clearance of parenchymal amyloid-? peptides. In the current work, we examined the changes in cortical microvascular structure and function in situ in TgCRND8, a transgenic mouse model of Alzheimer's disease. In contrast to venules, cortical arterioles were shown to increase in tortuosity and decrease in calibre with amyloid-? peptide accumulation. These structural changes were accompanied by progressive functional compromise, reflected in higher dispersion of microvascular network transit times, elongation of the transit times, and impaired microvascular reactivity to hypercapnia in the transgenic mice. Moreover, inhibition of amyloid-? peptide oligomerization and fibrillization via post-weaning administration of scyllo-inositol, a naturally occurring stereoisomer of myo-inositol, rescued both structural and functional impairment of the cortical microvasculature in this Alzheimer's disease model. These results demonstrate that microvascular impairment is directly correlated with amyloid-? accumulation and highlight the importance of targeting cerebrovascular amyloid angiopathy clearance for effective diagnosis, monitoring of disease progression and treatment of Alzheimer's disease.

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More information

Published date: October 2012
Keywords: cerebral amyloid angiopathy, vessel tortuosity, microvasculature, two-photon fluorescence microscopy, scyllo-inositol
Organisations: Faculty of Medicine

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Local EPrints ID: 353196
URI: http://eprints.soton.ac.uk/id/eprint/353196
ISSN: 0006-8950
PURE UUID: 7b4f063c-f077-43e4-87d5-86d88f59c38a

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Date deposited: 03 Jun 2013 13:12
Last modified: 16 Jul 2019 21:32

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Contributors

Author: A. Dorr
Author: B. Sahota
Author: L.V. Chinta
Author: M.E. Brown
Author: A.Y. Lai
Author: K. Ma
Author: C.A. Hawkes
Author: J. McLaurin
Author: B. Stefanovic

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