Amyloid-β-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-β peptides in the walls of leptomeningeal and cortical arterioles. These deposits are believed to result from impaired clearance of parenchymal amyloid-β 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-β 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-β 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-β accumulation and highlight the importance of targeting cerebrovascular amyloid angiopathy clearance for effective diagnosis, monitoring of disease progression and treatment of Alzheimer's disease.
Sunnybrook Research Institute, 2075 Bayview Avenue, Toronto, Ontario, Canada.
Adrienne
A
Dorr
Bhupinder
B
Sahota
Lakshminarayan V
LV
Chinta
Mary E
ME
Brown
Aaron Y
AY
Lai
Keran
K
Ma
Cheryl A
CA
Hawkes
JoAnne
J
McLaurin
Bojana
B
Stefanovic
D000544:Alzheimer Disease / Q000378:metabolism* / Q000503:physiopathology* / Q000628:therapy; D016229:Amyloid beta-Peptides / Q000502:physiology*; D000818:Animals; D001160:Arterioles / Q000473:pathology / Q000503:physiopathology; D001921:Brain / Q000098:blood supply* / Q000378:metabolism* / Q000503:physiopathology; D002196:Capillaries / Q000473:pathology / Q000503:physiopathology; D002533:Cerebral Angiography; D004195:Disease Models, Animal; D018450:Disease Progression; D051379:Mice; D057507:Mice, 129 Strain; D008822:Mice, Transgenic; D008833:Microcirculation / Q000502:physiology*; D014699:Venules / Q000473:pathology / Q000503:physiopathology
D016229:Amyloid beta-Peptides