Abstract
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 β3-integrin, a specific marker molecule of activated endothelium. The β3-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.
Similar content being viewed by others
References
Vaganuccui AH, Li WW (1994) Alzheimer’s disease and angiogenesis. The Lancet 361:605–608
in’t Veld BA, Ruitenberg A, Hofmann A et al. (2003) Nonsteroidal antiinflammatory drugs and the risk of Alzheimer’s disease. N Engl J Med 345:1515–21
Wolozin B, Kellman W, Ruosseau P et al. (2000) Decreased prevalence of Alzheimer disease associated with 3-hydroxy-3-methyglutaryl coenzyme A reductase inhibitors. Arch Neurol 57:1439–43
Selkoe DJ (1999) Translating cell biology into therapeutic advances in Alzheimer’s disease. Nature 399 (suppl):A23–31
McGeer PL, Schulzer M, McGeer EG (1996) Arthritis and anti-inflammatory agents as possible protective factors for Alzheimer’s disease: A review of 17 epidemiologic studies. Neurology 47:425–32
Liu F, Lau BH, Peng Q, Shah V (2000) Pycnogenol protects vascular endothelial cells from beta-amyloid-induced injury. Biol Pharm Bull 23:735–7
Gentile MT, Vecchione C, Maffei A et al. (2004) Mechanisms of soluble beta-amyloid impairment of endothelial function. J Biol Chem 279:48135–42
Kalaria RN, Cohen DL, Premkumar DR et al. (1998) Vascular endothelial growth factor in Alzheimer’s disease and experimental cerebral ischemia Brain. Res Mol Brain Res 62:101–5
Yang SP, Bae DG, Kang HJ, et al. (2004) Co-accumulation of vascular endothelial growth factor with beta-amyloid in the brain of patients with Alzheimer’s disease. Neurobiol Aging 25:283–90
Tarkowski E, Issa R, Sjogren M, et al. (2002) Increased intrathecal levels of the angiogenic factors VEGF and TGF-beta in Alzheimer’s disease and vascular dementia. Neurobiol Aging 23:237–23
Nagy JA, Vasile E, Feng D, et al. (2002) Vascular permeability factor/vascular endothelial growth factor induces lymphangiogenesis as well as angiogenesis. J Exp Med 196:1497–1506
Agorogiannis EI and Agorogiannis GI. Alzheimer’s disease and angiogenesis. The Lancet 2003; 361: 1299–300
Calhoun ME, Burgermeister P, Phinney AL et al. (1999) Neuronal overexpression of mutant amyloid precursor protein results in prominent deposition of cerebrovascular amyloid. Proc Natl Acad Sci USA 96:14088–93
Van-Dam D, D’Hooge R, Staufenbiel M, et al. (2003) Age-dependent cognitive decline in the APP23 model precedes amyloid deposition. Eur J Neurosci 17:388–96
Shattil SJ (1995) Function and regulation of the β3 integrins in hemostasis and vascular biology. Thromb Haemost 74:149–155
Lahorte CM, Vanderheyden JL, Steinmetz N, Van-de-Wiele C, Dierckx RA, Slegers G (2004) Apoptosis-detecting radioligands: Current state of the art and future perspectives. Eur J Nucl Med Mol Imaging 31:887–919
Haubner R, Weber WA, Beer AJ et al. Noninvasive visualization of the activated alphavbeta3 integrin in cancer patients by positron emission tomography and [18F]Galacto-RGD. PLoS Med 2005; 3:␣e70
Acknowledgements
The study was supported by the ‘Deutsche Forschungsgemeinschaft’ GRK 438 and by the ‘Konto für Klinische Forschung (KKF)’ of the Technical University of Munich. We thank Prof Dr M. Schwaiger and Prof Dr R. Senekowitsch-Schmidtke for support, as well as Sabrimol T. Astmer for helpful discussions.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Schultheiss, C., Blechert, B., Gaertner, F.C. et al. In vivo characterization of endothelial cell activation in a transgenic mouse model of Alzheimer’s disease. Angiogenesis 9, 59–65 (2006). https://doi.org/10.1007/s10456-006-9030-4
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10456-006-9030-4