27 August 2010. Several studies have shown that Alzheimer’s patients appear to be less susceptible to cancer, but the mechanism behind this association remains mysterious. A study in the August 25 Journal of Neuroscience may provide some clues. Researchers led by Michael Mullan at the Roskamp Institute in Sarasota, Florida, sought to answer the question of whether the Alzheimer’s brain is fundamentally pro-angiogenic or anti-angiogenic. They implanted gliomas into the brains of two AD mouse models, and found less tumor growth and angiogenesis in these animals than in similarly treated wild-type mice, implying that on balance, these AD mouse brains were anti-angiogenic. The results may shed light not only on the apparent suppression of cancer in AD patients, but also on the complex relationship between AD and vascular factors.
Several studies have found that vascular damage can exacerbate AD (see, e.g., Snowdon et al., 1997 and Petrovich et al., 2000), perhaps by decreasing the clearance of Aβ across the blood-brain barrier (see ARF related news story on Bell et al., 2009). The main genetic risk factor for AD, ApoE4, is also a risk factor for cardiovascular conditions, and abnormalities in brain blood vessels are common in people with Alzheimer’s. AD brains contain elevated levels of several pro-angiogenic growth factors such as VEGF and bFGF, but they also contain anti-angiogenic factors such as endostatin (see Deininger et al., 2002). In previous work, Mullan and colleagues showed that soluble Aβ peptides themselves are anti-angiogenic (see Paris et al., 2004; Paris et al., 2005; Patel et al., 2008). Because of this mix of factors that promote and suppress blood vessel growth, it was not clear whether the AD brain was a favorable environment for angiogenesis, as some have speculated, or not.
To address this question, first author Daniel Paris implanted invasive GL261 murine gliomas, known to induce vascularization, into the right frontal lobes of AD mice expressing APP carrying the Swedish mutation (Tg2576), double transgenic mice carrying both APPswe and a presenilin-1 mutation (TgPS1/APPswe), and wild-type littermates. Tumors were allowed to grow for three weeks before analysis. Paris and colleagues found that tumor volumes were reduced by about half in the AD mice compared to wild-type, and that within the tumors, vascular density was also about half as much in the AD mice, indicating that vascularization and tumor growth were impaired. Paris and colleagues also showed in vitro that brain homogenates from the AD mice inhibited the formation of capillaries by human brain microvascular cells, both alone and in the presence of glioma cells. The results suggest that, at least in these mouse models, the AD brain is predominantly anti-angiogenic.
“This is a fascinating study,” suggested Cathy Roe of Washington University in St. Louis, Missouri, in an e-mail to ARF. Roe’s work has shown an inverse epidemiological link between Alzheimer’s and several types of cancer (see ARF related news story). “An amyloid-β-related mechanism that affects tumor growth and vascularization, as suggested by the results of Paris et al., would provide an explanation for an inverse relationship between AD and solid-tumor cancers at many sites,” she wrote (see full comment below).
Thomas Bayer, of the University of Göttingen in Germany, said that the tumor growth inhibition effects in this study appear robust, but noted there are some unanswered questions. The double-transgenic mouse model has a much higher level of Aβ in its brain than does the Tg2576 mouse, Bayer said, so it would be interesting to know why the double-transgenic does not show greater tumor inhibition than the Tg2576 mouse. Bayer said it will also be important to study the molecular mechanisms of how Aβ is able to interfere with vascular function.
The new findings help to flesh out the picture of AD, angiogenesis, and vascular insults, implying that not only does vascular damage contribute to AD neurodegeneration, but also that AD brains may be especially poorly equipped to repair such damage. In an e-mail to ARF, Paris wrote, “This may explain why vascular insults, such as a stroke, have particularly devastating effects in AD brains.” Their work also suggests, Paris wrote, that “Therapies stimulating brain vascularization may be beneficial in AD patients. We are developing different methodologies to stimulate angiogenesis in the brains of transgenic mouse models of AD, with the hope that certain of these approaches could be useful for the treatment of AD.”—Madolyn Bowman Rogers.
Paris D, Ganey N, Banasiak M, Laporte V, Patel N, Mullan M, Murphy SF, Yee GT, Bachmeier C, Ganey C, Beaulieu-Abdelahad D, Mathura VS, Brem S, Mullan M. Impaired orthotopic glioma growth and vascularization in transgenic mouse models of Alzheimer’s disease. J Neurosci Aug 25, 2010;30(34);11251-58. Abstract