title: Impaired orthotopic glioma growth and vascularization in transgenic mouse models of Alzheimer's disease.
abstract: 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.
authors.affiliation: The Roskamp Institute, Sarasota, Florida 34243, USA. dparis@rfdn.org
authors.forename: Daniel
authors.initials: D
authors.lastname: Paris
authors.forename: Nowel
authors.initials: N
authors.lastname: Ganey
authors.forename: Magdalena
authors.initials: M
authors.lastname: Banasiak
authors.forename: Vincent
authors.initials: V
authors.lastname: Laporte
authors.forename: Nikunj
authors.initials: N
authors.lastname: Patel
authors.forename: Myles
authors.initials: M
authors.lastname: Mullan
authors.forename: Susan F
authors.initials: SF
authors.lastname: Murphy
authors.forename: Gi-Taek
authors.initials: GT
authors.lastname: Yee
authors.forename: Corbin
authors.initials: C
authors.lastname: Bachmeier
authors.forename: Christopher
authors.initials: C
authors.lastname: Ganey
authors.forename: David
authors.initials: D
authors.lastname: Beaulieu-Abdelahad
authors.forename: Venkatarajan S
authors.initials: VS
authors.lastname: Mathura
authors.forename: Steven
authors.initials: S
authors.lastname: Brem
authors.forename: Michael
authors.initials: M
authors.lastname: Mullan
mesh_terms: 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