Cerebral circulation: function and dysfunction in Alzheimer's disease.
Alzheimer's disease is a neurodegenerative disease associated with a cerebrovascular pathology partly imputed to increased brain levels of amyloid beta (Aβ) peptide and transforming growth factor-β1 (TGF-β1). Using transgenic mice that overproduce Aβ (APP mice) or TGF-β1 (TGF mice), we found that both induce impairments of cerebrovascular function and structural changes of the vessel wall. Soluble Aβ species affect blood vessel primarily by increasing oxidative stress, which results in reduced nitric oxide-mediated dilations and impaired signaling of endothelial transient receptor potential vanilloid type 4 and smooth muscle KATP channels. These impairments occur early in the disease process and can be rescued by either antioxidants (Tempol, N-acetylcysteine) or therapy with antioxidant properties (simvastatin). In contrast, comparable impairments in TGF mice were insensitive to antioxidants and could only be rescued by therapy with pleiotropic effects. The blood flow response evoked by whisker stimulation was impaired in both APP and TGF mice. In contrast, the cerebral uptake of glucose induced by this stimulus was reduced only in APP mice, pointing to preserved neuronal function in the TGF mice. Accordingly, despite similar but mechanistically different cerebrovascular deficits in APP and TGF mice, overt cognitive deficits were seen only in APP mice and could be rescued depending on age.
Laboratory of Cerebrovascular Research, Montreal Neurological Institute, McGill University, Montréal, Québec, Canada.
Edith
E
Hamel
D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D001808:Blood Vessels / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D001921:Brain / Q000378:metabolism*; D002560:Cerebrovascular Circulation; D003071:Cognition / Q000502:physiology*; D004195:Disease Models, Animal; D054086:KATP Channels / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D018384:Oxidative Stress / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D000975:Antioxidants; D054086:KATP Channels; D053773:Transforming Growth Factor beta1