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The Journal of Neuroscience, January 24, 2007, 27(4):824-831; doi:10.1523/JNEUROSCI.4345-06.2007

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Neurobiology of Disease
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

Cristina Lopez-Lopez,^1,2 Marcelo O. Dietrich,¹ Friedrich Metzger,² Hansruedi Loetscher,² and Ignacio Torres-Aleman¹

¹Laboratory of Neuroendocrinology, Cajal Institute, Consejo Superior de Investigaciones Científicas, 28002 Madrid, Spain, and ²Hoffmann-LaRoche, CNS Preclinical Research, CH-4070 Basel, Switzerland

Correspondence should be addressed to Ignacio Torres-Aleman, Cajal Institute, Consejo Superior de Investigaciones Científicas, Avenida Doctor Arce, 37, 28002 Madrid, Spain. Email: torres{at}cajal.csic.es

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.

Key words: brain endothelial cells; Alzheimer's disease; insulin-like growth factor I; AMPK; vascular endothelial growth factor; intracellular signaling

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Received July 3, 2006; revised Oct. 31, 2006; accepted Nov. 3, 2006.

Correspondence should be addressed to Ignacio Torres-Aleman, Cajal Institute, Consejo Superior de Investigaciones Científicas, Avenida Doctor Arce, 37, 28002 Madrid, Spain. Email: torres{at}cajal.csic.es

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