Impaired orthotopic glioma growth and vascularization in transgenic mouse models of Alzheimer's disease.
Alzheimer's disease (AD) is the most common form of dementia among the aging population and is characterized pathologically by the progressive intracerebral accumulation of beta-amyloid (Abeta) peptides and neurofibrillary tangles. The level of proangiogenic growth factors and inflammatory mediators with proangiogenic activity is known to be elevated in AD brains which has led to the supposition that the cerebrovasculature of AD patients is in a proangiogenic state. However, angiogenesis depends on the balance between proangiogenic and antiangiogenic factors and the brains of AD patients also show an accumulation of endostatin and Abeta peptides which have been shown to be antiangiogenic. To determine whether angiogenesis is compromised in the brains of two transgenic mouse models of AD overproducing Abeta peptides (Tg APPsw and Tg PS1/APPsw mice), we assessed the growth and vascularization of orthotopically implanted murine gliomas since they require a high degree of angiogenesis to sustain their growth. Our data reveal that intracranial tumor growth and angiogenesis is significantly reduced in Tg APPsw and Tg PS1/APPsw mice compared with their wild-type littermates. In addition, we show that Abeta inhibits the angiogenesis stimulated by glioma cells when cocultured with human brain microvascular cells on a Matrigel layer. Altogether our data suggest that the brain of transgenic mouse models of AD does not constitute a favorable environment to support neoangiogenesis and may explain why vascular insults synergistically precipitate the cognitive presentation of AD.
Paris
Daniel
D
The Roskamp Institute, Sarasota, Florida 34243, USA. dparis@rfdn.org
Ganey
Nowel
N
Banasiak
Magdalena
M
Laporte
Vincent
V
Patel
Nikunj
N
Mullan
Myles
M
Murphy
Susan F
SF
Yee
Gi-Taek
GT
Bachmeier
Corbin
C
Ganey
Christopher
C
Beaulieu-Abdelahad
David
D
Mathura
Venkatarajan S
VS
Brem
Steven
S
Mullan
Michael
M
D000544:Alzheimer Disease / Q000235:genetics / Q000473:pathology* / Q000517:prevention & control; D000818:Animals; D001932:Brain Neoplasms / Q000098:blood supply* / Q000473:pathology* / Q000517:prevention & control; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D018920:Coculture Techniques; D006224:Cricetinae; D004195:Disease Models, Animal; D005910:Glioma / Q000235:genetics / Q000473:pathology* / Q000517:prevention & control; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009368:Neoplasm Transplantation / Q000379:methods / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000473:pathology* / Q000517:prevention & control