Disturbed Cross Talk between Insulin-Like Growth Factor I and AMP-Activated Protein Kinase as a Possible Cause of Vascular Dysfunction in the Amyloid Precursor Protein/Presenilin 2 Mouse Model of Alzheimer's Disease

Laboratory of Neuroendocrinology, Cajal Institute, Consejo Superior de Investigaciones Científicas, 28002 Madrid, Spain.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 02/2007; 27(4):824-31. DOI: 10.1523/JNEUROSCI.4345-06.2007
Source: PubMed


Cerebrovascular dysfunction appears to be involved in Alzheimer's disease (AD). In double mutant amyloid precursor protein/presenilin 2 (APP/PS2) mice, a transgenic model of AD, vessel homeostasis is disturbed. These mice have elevated levels of vascular endothelial growth factor (VEGF) and increased brain endothelial cell division but abnormally low brain vessel density. Examination of the potential involvement of insulin-like growth factor I (IGF-I) in these alterations revealed that treatment with IGF-I, a potent vessel growth promoter in the brain that ameliorates cognitive dysfunction in APP/PS2 mice, counteracted vascular dysfunction as follows: VEGF levels and endothelial cell proliferation were reduced, whereas vascular density was normalized. Notably, abnormally elevated brain IGF-I receptor levels in APP/PS2 mice were also normalized by IGF-I treatment. Analysis of possible processes involved in these alterations indicated that AMP-activated protein kinase (AMPK), a cell energy sensor that intervenes in angiogenic signaling and interacts with IGF-I, was also abnormally activated in APP/PS2 brains. Examination of the consequences of AMPK activation on cultured brain endothelial cells revealed increased VEGF levels together with enhanced endothelial cell proliferation and metabolism. Although these effects were also independently elicited by IGF-I, when both IGF-I and AMPK pathways were simultaneously activated on brain endothelial cells, VEGF production and endothelial cell proliferation ceased while cells remained metabolically activated (glucose use, peroxide production, and mitochondrial activity were elevated) and became more resistant to oxidative stress. Therefore, high IGF-I receptor and phosphoAMPK levels in APP/PS2 brains may reflect imbalanced IGF-I and AMPK angiogenic cross talk that could underlie vascular dysfunction in this model of AD.

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Available from: Ignacio Torres-Aleman, Feb 04, 2014
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    • "However, in pathologic hypothesis for AD, there has been growing interest on the insulin signaling, and insulin resistance is involved in the pathogenesis of cognitive deficits in the neurodegenerative diseases (Hoyer, 2004; de la Nonte and Wands, 2005; Salkovic-Petrisic and Hoyer, 2007). The insulin-resistant brain state is thought to play a pivotal role in the pathogenesis of neurodegenerative disorders including AD (Lopez-Lopez et al., 2007). In particular, alteration of energy metabolism by enhancing of insulin resistance changes the memory function with decrement of neuronal growth factors in the brain (Dietrich et al., 2008; Freiherr et al., 2013). "
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    04/2014; 10(2):81-8. DOI:10.12965/jer.140102
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    • "Since the discovery of AMPK's cytopathological role in mitochondrially diseased Dictyostelium cells, research in other systems has been published which supports the hypothesis that chronic activation of AMPK can cause cytopathological outcomes. Mitochondrial dysfunction is a feature of many neurodegenerative diseases and in some of these -Amyotrophic Lateral Sclerosis (ALS), Alzheimer's and Huntington's Disease -activation of AMPK has been confirmed to occur as predicted from the Dictyostelium model [17] [18] [19]. "
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    • "Accordingly, the reduction of endothelial RAGE levels by EPO might have important therapeutic implications that warrants further investigation. Alzheimer's disease brains show neurovascular dysfunction , degraded capillary networks, and impaired angiogenesis , which possibly impair memory by decreasing brain perfusion and accelerating Ab accumulation (Lopez-Lopez et al. 2007; Zlokovic 2005). Accordingly, the enhancement of angiogenesis by EPO may have contributed to neurovascular regeneration in AD brains. "
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