The role of the Vascular Endothelial Growth Factor (VEGF) in processing of the β-amyloid precursor protein
Cerebrovascular abnormalities such as thickening of the microvascular basement membranes, decreased luminal diameter (Vinters et al., 1996, Claudio, 1996; Ellis et al., 1996; Kalaria and Hedera, 1995; Kalaria and Pax, 1995; Mancardi et al., 1980), cerebral amyloid angiopathy, and microvascular endothelial degeneration (de la Torre et al., 2002; Kalaria, 2000; Soffer, 2006; Thomas et al., 1996) have frequently been observed in Alzheimer patients, from which a causal relationship between vascular mechanisms and the development of sporadic Alzheimer’s disease (AD) has been hypothesized (de la Torre and Mussivand, 1993, for reviews, see de la Torre, 2008, Isingrini et al., 2009).
There are a number of studies providing evidence that the cerebrovascular degenerations in AD are related to β-amyloid (Aβ) deposition (Attems et al., 2004; Buee et al., 1994, 1997; Fischer et al., 1990; Kalaria, 1998, 2002; Mann et al., 1986; Suter et al., 2002). Aβ may cause degeneration of both the larger perforating arterial vessels as well as cerebral capillaries, which may severely affect brain perfusion and blood brain barrier (for review, see e.g., Kalaria, 2002). Moreover, Aβ peptides have been described to inhibit angiogenesis both in vitro and in vivo (Paris et al., 2004a,b), and deregulation of angiogenic factors may contribute to various neurological disorders including neurodegeneration (for review, see Ruiz de Almodovar et al., 2009). One of the key angiogenic factor, the vascular endothelial
growth factor (VEGF), a highly conserved heparin-binding protein (Sun and Guo, 2005), was originally found in vascular endothelial cells and is able to induce vascular endothelial cell proliferation, migration and vasopermeability in many types of tissue (Ferrara et al., 2003).
Increased intrathecal levels of VEGF have also been observed in brains of Alzheimer patients as compared to age-matched healthy individuals (Kalaria et al., 1998; Tarkowski et al., 2002; Yang et al., 2004) that has been correlated with the clinical severity of the disease (Ryu et al., 2009). However, the functional significance of VEGF up-regulation in the pathogenesis and progression of AD is still a matter of debate. While VEGF and other angiogenic factors were found to be enhanced in AD (Pogue and Lukiw, 2004; Thirumangalakudi et al., 2006; Vagnucci and Li, 2003; Desai et al., 2009), there is little evidence of neovascularization in AD brain but considerable cerebrovascular abnormalities and degenerations (see, e.g. Zipser et al., 2007). Only in the hippocampus of AD patients the ongoing angiogenesis resulted in increased vascular density compared with controls (Desai et al., 2009).
It is assumed that the microvascular degenerations in AD may also be the consequence of the vasoactive detrimental effects of Aβ (Schultheiss et al., 2006; for review, see e.g., Cole and Vassar, 2008). Otherwise, there are also reports that ischemia and hypofusion may trigger accumulation and cleavage of the amyloid precursor protein into Aβ, and its deposition in the brain (Bennett et al., 2000; Jendroska et al., 1995), while the mechanisms through which these pathologies affect β-amyloidogenesis are largely unknown. The upregulation of VEGF in response to hypoxic, ischemic or hypoglycemic stress (Marti et al., 1998, 2000; Stein et al., 1995; Yancopoulos et al. 2000) suggests its involvement also in processing of the amyloid precursor protein (APP). In turn, APP is also highly expressed in the endothelium of neoforming vessels (Paris et al., 2005), and inhibitors of α-and β-secretases have been reported to inhibit angiogenesis and tumour growth (Paris et al., 2005), suggesting a role of APP metabolism also during angiogenesis. Recently, VEGF has been shown to also be involved in the induction of microglial-mediated inflammation by Aβ deposits via the microglial VEGF receptor subtype Flt-1 serving as a chemotactic receptor to mobilize microglial cells (Ryu et al., 2009).
As vascular endothelial cells are also capable to express and to secrete APP (Ciallella et al., 1999), it has been hypothesized that VEGF may also be involved in formation and deposition of Aβ. In conclusion, all the observations mentioned above prompted us to address the hypothesis whether VEGF, in addition to its angiogenic, neuroprotective and neurogenic actions, may also play a role in APP processing and in formation and deposition of β-amyloid in AD.
The project proposal stresses the hypothesis that VEGF up-regulated in AD, may also play a role in the progression of the disease by affecting the processing of APP.
For testing this hypothesis, the following objectives will be addressed:
Objective 1: Does VEGF affect APP metabolism in vitro?
Objective 2: Does VEGF exert its effect on APP processing in a cell-type specific manner?
Objective 3: Does VEGF exert its action on neuronal APP metabolism in an indirect manner through selectively activating endothelial cells.
Objective 4: Does VEGF induce or trigger aggregation and fibrillogenesis of β-amyloid?
Finally, at the end of the project, the possibility of a comprehensive picture about the relationship between VEGF and the increase of β-amyloid in Alzheimer's disease will help to answer the question whether the use of drugs targeting VEGF-mediated actions in the brain, represents a strategy to prevent or to treat AD.