In vivo characterization of endothelial cell activation in a transgenic mouse model of Alzheimer's disease.
Alzheimer's disease (AD) is the most common cause of dementia worldwide. AD is characterized by an excessive cerebral amyloid deposition leading to degeneration of neurons and eventually to dementia. It has been shown by epidemiological studies that cardiovascular drugs with an anti-angiogenic effect can influence the outcome of AD patients. Therefore, it has been speculated that in AD angiogenesis in the brain vasculature may play an important role. Here we report that in the brain of APP23 mice--a transgenic model of AD--after deposition of amyloid in blood vessels endothelial cell activation occurs in an age-dependent manner. Amyloid deposition is followed by the expression of beta3-integrin, a specific marker molecule of activated endothelium. The beta3-integrin expression is restricted to amyloid-positive vessels. Moreover, homogenates of the brains of APP23 mice induced the formation of new vessels in an in vivo angiogenesis assay. Vessel formation could be blocked by the VEGF antagonist SU 4312 as well as by statins, suggesting that these drugs may interfere with endothelial cell activation in AD. In conclusion our results indicate that amyloid deposition in the vasculature leads to endothelial cell apoptosis and endothelial cell activation, which can be modulated by anti-angiogenic drugs.
Schultheiss
Caroline
C
Nuklearmedizinische Klinik und Poliklinik, Technische Universität München, München, Germany.
Blechert
Birgit
B
Gaertner
Florian C
FC
Drecoll
Enken
E
Mueller
Jan
J
Weber
Georg F
GF
Drzezga
Alexander
A
Essler
Markus
M
D000375:Aging / Q000502:physiology*; D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D000682:Amyloid / Q000096:biosynthesis; D000818:Animals; D001808:Blood Vessels / Q000737:chemistry / Q000378:metabolism; D001923:Brain Chemistry; D002021:Buffers; D003094:Collagen / Q000378:metabolism; D004195:Disease Models, Animal; D004338:Drug Combinations; D042783:Endothelial Cells / Q000378:metabolism*; D006863:Hydrogen-Ion Concentration; D007150:Immunohistochemistry; D039661:Integrin beta3 / Q000235:genetics / Q000378:metabolism; D007797:Laminin / Q000378:metabolism; D008297:Male; D008706:Methemoglobin / Q000032:analysis; D051379:Mice; D008822:Mice, Transgenic; D018919:Neovascularization, Physiologic / Q000235:genetics; D011509:Proteoglycans / Q000378:metabolism; D013997:Time Factors
D000682:Amyloid; D002021:Buffers; D004338:Drug Combinations; D039661:Integrin beta3; D007797:Laminin; D011509:Proteoglycans; C059485:matrigel; D003094:Collagen; D008706:Methemoglobin