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 ␤-amyloid (A␤) 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 A␤ 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 A␤ 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 A␤ 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.

Human Apolipoprotein E ε4 Expression Impairs Cerebral Vascularization and Blood—Brain Barrier Function in Mice

“…29,30 In line with these observations, implanted glioma tumors in the brains of two transgenic mouse models of AD (Tg APPsw and Tg PS1/APPsw mice) showed a 50% decrease in blood vessel density compared with implanted tumors in the brains of wild-type mice. 31 Consistently, a reduction in the basement membrane surface area was observed in postmortem data of individuals carrying APOE4 genotype comparatively to APOE3. 32 As pointed out above, the volume of distribution of [ 14 C]-sucrose after intracarotid perfusion remained close to 15 μL/g across all groups, suggesting that the reduction in cerebral vascularization was not associated with an alteration in the vascular volume.…”

Kallikrein‐8 inhibition attenuates Alzheimer's disease pathology in mice

“…Given that all the aforementioned behavioral, molecular, and structural processes, that is, anxiety and cognition, neuronal [9,10], and vascular [11,12] plasticity, as well as autophagy [13,14] are also impaired in Alzheimer's disease (AD) patients and transgenic mice, it seems likely that KLK8/EPHB2 signaling could be involved in the pathogenesis of AD, although hitherto very few studies support this hypothesis. KLK8 mRNA [15] is up-regulated in AD-affected human hippocampus, and hippocampal EPHB2 is reduced in AD patients and in hAPP mice [16,17].…”

Hypoxia induces angiogenic factors in brain microvascular endothelial cells

“…Despite increases in several pro-angiogenic factors in the AD brain, evidence for increased vascularity in AD is lacking. On the contrary, it has been suggested the angiogenic process is delayed and/or impaired in aged tissues, with several studies showing decreased microvascular density in the AD brain (Buee et al, 1994; 1997; Edelber and Reed, 2003; Paris et al, 2010,). Therefore, lack of vessel formation despite the increase in pro-angiogenic factors evoked by hypoxia suggests these angiogenic factors are not sufficient for the completion of the angiogenic process and the development of new vessels by brain endothelial cells.…”

“…A growing literature shows biochemical and functional changes in the cerebrovasculature in AD including expression and/or release of proteins related to vascular endothelial activation and angiogenesis such as VEGF, ET-1, HIF-1α, and thrombin (Grammas et al, 2006; Thirumangalakudi et al, 2006; Luo and Grammas, 2010; Yin et al, 2010). However, the function of angiogenic proteins in the AD brain is unknown and their significance is controversial (Bell and Zlokovic, 2009; Grammas, 2011; Paris et al, 2010., Wu et al, 2005). Understanding the effects of hypoxia on brain endothelial cells is important to determining mechanisms of hypoxia-induced damage in the brain and its links to AD.…”