The Complexity of Sporadic Alzheimer’s Disease Pathogenesis: The Role of RAGE as Therapeutic Target to Promote Neuroprotection by Inhibiting Neurovascular Dysfunction
Alzheimer's disease (AD) is the most common cause of dementia. Amyloid plaques and neurofibrillary tangles are prominent pathological features of AD. Aging and age-dependent oxidative stress are the major nongenetic risk factors for AD. The beta-amyloid peptide (Aβ), the major component of plaques, and advanced glycation end products (AGEs) are key activators of plaque-associated cellular dysfunction. Aβ and AGEs bind to the receptor for AGEs (RAGE), which transmits the signal from RAGE via redox-sensitive pathways to nuclear factor kappa-B (NF-κB). RAGE-mediated signaling is an important contributor to neurodegeneration in AD. We will summarize the current knowledge and ongoing studies on RAGE function in AD. We will also present evidence for a novel pathway induced by RAGE in AD, which leads to the expression of thioredoxin interacting protein (TXNIP), providing further evidence that pharmacological inhibition of RAGE will promote neuroprotection by blocking neurovascular dysfunction in AD. 1. Introduction Alzheimer’s disease (AD) pathology is characterized in by the presence of several kinds of amyloid plaques and neurofibrillary tangles in the brain, which are mainly composed by the beta amyloid (Aβ), derived from the proteolytic cleavage of the amyloid precursor protein (APP), and hyperphosphorylated tau [1]. AD can be subdivided in 2 major forms: (i) familial AD, which represents rare early onset forms due to gene mutations leading to enhanced Aβ production or faster aggregating Aβ peptide; (ii) sporadic AD forms, which represent about 95% of AD cases [2]. The pathogenesis of sporadic AD is extremely complex, and its ultimate cause is still under debate. Epidemiological studies reveal growing evidence that most cases of sporadic AD likely involve a combination of genetic and environmental risk factors. However, the only risk factors so far validated for late-onset disease are age, family history, and the susceptibility gene ApoE4 allele [3]. A hallmark of the aged brain is the presence of oxidative stress [4]. Aβ fibrils are toxic by generating oxygen free radicals in the absence of any cellular element [5, 6]. However, synaptic dysfunction and behavioral changes in AD precede the formation of large Aβ aggregates and fibrils. Indeed, Aβ dimers and soluble oligomers are considered the major toxic form [7, 8], while fibrils-induced oxidative stress operates late in the course of AD. Thus, the mechanisms through which Aβ exerts its toxic effect at the early stages of AD remain still to be clarified. Recent evidences suggest that age-relate cofactors
References
[1]
J. Hardy and D. J. Selkoe, “The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics,” Science, vol. 297, no. 5580, pp. 353–356, 2002.
[2]
A. Kern and C. Behl, “The unsolved relationship of brain aging and late-onset Alzheimer disease,” Biochimica et Biophysica Acta, vol. 1790, pp. 1124–1232, 2009.
[3]
C. Qiu, M. Kivipelto, and E. Von Strauss, “Epidemiology of Alzheimer's disease: occurrence, determinants, and strategies toward intervention,” Dialogues in Clinical Neuroscience, vol. 11, no. 2, pp. 111–128, 2009.
[4]
M. Recuero, M. C. Vicente, A. Martínez-García et al., “A free radical-generating system induces the cholesterol biosynthesis pathway: a role in Alzheimer's disease,” Aging Cell, vol. 8, no. 2, pp. 128–139, 2009.
[5]
P. Faller, “Copper and zinc binding to amyloid-β: coordination, dynamics, aggregation, reactivity and metal-ion transfer,” ChemBioChem, vol. 10, no. 18, pp. 2837–2845, 2009.
[6]
L. Perrone, E. Mothes, M. Vignes et al., “Copper transfer from Cu-Aβ to human serum albumin inhibits aggregation, radical production and reduces Aβ toxicity,” ChemBioChem, vol. 11, no. 1, pp. 110–118, 2010.
[7]
S. Lesné, L. Kotilinek, and K. H. Ashe, “Plaque-bearing mice with reduced levels of oligomeric amyloid-β assemblies have intact memory function,” Neuroscience, vol. 151, no. 3, pp. 745–749, 2008.
[8]
D. J. Selkoe, “Soluble oligomers of the amyloid β-protein impair synaptic plasticity and behavior,” Behavioural Brain Research, vol. 192, no. 1, pp. 106–113, 2008.
[9]
A. Bierhaus and P. P. Nawroth, “The Alzheimer's disease-diabetes angle: inevitable fate of aging or metabolic imbalance limiting successful aging,” Journal of Alzheimer's Disease, vol. 16, no. 4, pp. 673–675, 2009.
[10]
S. Takeda, N. Sato, K. Uchio-Yamada et al., “Diabetes-accelerated memory dysfunction via cerebrovascular inflammation and Aβ deposition in an Alzheimer mouse model with diabetes,” Proceedings of the National Academy of Sciences of the United States of America, vol. 107, no. 15, pp. 7036–7041, 2010.
[11]
T. Valente, A. Gella, X. Fernàndez-Busquets, M. Unzeta, and N. Durany, “Immunohistochemical analysis of human brain suggests pathological synergism of Alzheimer's disease and diabetes mellitus,” Neurobiology of Disease, vol. 37, no. 1, pp. 67–76, 2010.
[12]
A. Bierhaus, M. A. Hofmann, R. Ziegler, and P. P. Nawroth, “AGEs and their interaction with AGE-receptors in vascular disease and diabetes mellitus. I. The AGE concept,” Cardiovascular Research, vol. 37, no. 3, pp. 586–600, 1998.
[13]
A. Rahmadi, N. Steiner, and G. Münch, “Advanced glycation endproducts as gerontotoxins and biomarkers for carbonyl-based degenerative processes in Alzheimer's disease,” Clinical Chemistry and Laboratory Medicine, vol. 49, no. 3, pp. 385–391, 2011.
[14]
C. Loske, A. Gerdemann, W. Schepl et al., “Transition metal-mediated glycoxidation accelerates cross-linking of β- amyloid peptide,” European Journal of Biochemistry, vol. 267, no. 13, pp. 4171–4178, 2000.
[15]
M. P. Vitek, K. Bhattacharya, J. M. Glendening et al., “Advanced glycation end products contribute to amyloidosis in Alzheimer disease,” Proceedings of the National Academy of Sciences of the United States of America, vol. 91, no. 11, pp. 4766–4770, 1994.
[16]
M. Guglielmotto, M. Aragno, E. Tamagno et al., “AGEs/RAGE complex upregulates BACE1 via NF-κB pathway activation,” Neurobiology of Aging, vol. 33, no. 1, pp. 196.e13–196.e27, 2012.
[17]
A. Bierhaus, P. M. Humpert, M. Morcos et al., “Understanding RAGE, the receptor for advanced glycation end products,” Journal of Molecular Medicine, vol. 83, no. 11, pp. 876–886, 2005.
[18]
A. Bierhaus and P. P. Nawroth, “Multiple levels of regulation determine the role of the receptor for AGE (RAGE) as common soil in inflammation, immune responses and diabetes mellitus and its complications,” Diabetologia, vol. 52, no. 11, pp. 2251–2263, 2009.
[19]
S. D. Yan, A. Roher, M. Chaney, B. Zlokovic, A. M. Schmidt, and D. Stern, “Cellular cofactors potentiating induction of stress and cytotoxicity by amyloid β-peptide,” Biochimica et Biophysica Acta, vol. 1502, no. 1, pp. 145–157, 2000.
[20]
A. M. Schmidt, B. Sahagan, R. B. Nelson, J. Selmer, R. Rothlein, and J. M. Bell, “The role of RAGE in amyloid-β peptide-mediated pathology in Alzheimer's disease,” Current Opinion in Investigational Drugs, vol. 10, no. 7, pp. 672–680, 2009.
[21]
D. Y. Shi, A. Bierhaus, P. P. Nawroth, and D. M. Stern, “RAGE and Alzheimer's disease: a progression factor for amyloid-β- induced cellular perturbation?” Journal of Alzheimer's Disease, vol. 16, no. 4, pp. 833–843, 2009.
[22]
R. Deane, R. D. Bell, A. Sagare, and B. V. Zlokovic, “Clearance of amyloid-β peptide across the blood-brain barrier: implication for therapies in Alzheimer's disease,” CNS and Neurological Disorders—Drug Targets, vol. 8, no. 1, pp. 16–30, 2009.
[23]
R. Deane, S. D. Yan, R. K. Submamaryan et al., “RAGE mediates amyloid-β peptide transport across the blood-brain barrier and accumulation in brain,” Nature Medicine, vol. 9, no. 7, pp. 907–913, 2003.
[24]
R. Deane and B. V. Zlokovic, “Role of the blood-brain barrier in the pathogenesis of Alzheimer's disease,” Current Alzheimer Research, vol. 4, no. 2, pp. 191–197, 2007.
[25]
J. Daborg, M. Von Otter, A. Sj？lander et al., “Association of the RAGE G82S polymorphism with Alzheimer's disease,” Journal of Neural Transmission, vol. 117, no. 7, pp. 861–867, 2010.
[26]
L. Perrone, T. S. Devi, K. I. Hosoya, T. Terasaki, and L. P. Singh, “Thioredoxin interacting protein (TXNIP) induces inflammation through chromatin modification in retinal capillary endothelial cells under diabetic conditions,” Journal of Cellular Physiology, vol. 221, no. 1, pp. 262–272, 2009.
[27]
O. Sbai, T. S. Devi, M. A. B. Melone et al., “RAGE-TXNIP axis is required for S100B-promoted Schwann cell migration, fibronectin expression and cytokine secretion,” Journal of Cell Science, vol. 123, no. 24, pp. 4332–4339, 2010.
[28]
S. Y. Kim, H. W. Suh, J. W. Chung, S. R. Yoon, and I. Choi, “Diverse functions of VDUP1 in cell proliferation, differentiation, and diseases,” Cellular & molecular immunology, vol. 4, no. 5, pp. 345–351, 2007.
[29]
G. Marcon, G. Tell, L. Perrone et al., “APE1/Ref-1 in Alzheimer's disease: an immunohistochemical study,” Neuroscience Letters, vol. 466, no. 3, pp. 124–127, 2009.
[30]
L. Perrone, T. S. Devi, K. I. Hosoya, T. Terasaki, and L. P. Singh, “Thioredoxin interacting protein (TXNIP) induces inflammation through chromatin modification in retinal capillary endothelial cells under diabetic conditions,” Journal of Cellular Physiology, vol. 221, no. 1, pp. 262–272, 2010.
[31]
H. Yamawaki, S. Pan, R. T. Lee, and B. C. Berk, “Fluid shear stress inhibits vascular inflammation by decreasing thioredoxin-interacting protein in endothelial cells,” Journal of Clinical Investigation, vol. 115, no. 3, pp. 733–738, 2005.
[32]
M. L. Aon-Bertolino, J. I. Romero, P. Galeano et al., “Thioredoxin and glutaredoxin system proteins-immunolocalization in the rat central nervous system,” Biochimica et Biophysica Acta, vol. 1810, no. 1, pp. 93–110, 2011.
[33]
S. Craft, “Insulin resistance and Alzheimer's disease pathogenesis: potential mechanisms and implications for treatment,” Current Alzheimer Research, vol. 4, no. 2, article 21, pp. 147–152, 2007.
[34]
W. A. Chutkow, A. L. Birkenfeld, J. D. Brown et al., “Deletion of the α-arrestin protein Txnip in mice promotes adiposity and adipogenesis while preserving insulin sensitivity,” Diabetes, vol. 59, no. 6, pp. 1424–1434, 2010.
[35]
L. Wang, S. Li, and F. B. Jungalwala, “Receptor for advanced glycation end products (RAGE) mediates neuronal differentiation and neurite outgrowth,” Journal of Neuroscience Research, vol. 86, no. 6, pp. 1254–1266, 2008.
[36]
D. Harman, “The aging process,” Proceedings of the National Academy of Sciences of the United States of America, vol. 78, no. 11, pp. 7124–7128, 1981.
[37]
K. B. Beckman and B. N. Ames, “The free radical theory of aging matures,” Physiological Reviews, vol. 78, no. 2, pp. 547–581, 1998.
[38]
T. H. Fleming, P. M. Humpert, P. P. Nawroth, and A. Bierhaus, “Reactive metabolites and AGE/RAGE-mediated cellular dysfunction affect the aging process—a mini-review,” Gerontology, vol. 57, no. 5, 2010.
[39]
D. A. Butterfield and R. Sultana, “Redox proteomics identification of oxidatively modified brain proteins in Alzheimer's disease and mild cognitive impairment: insights into the progression of this dementing disorder,” Journal of Alzheimer's Disease, vol. 12, no. 1, pp. 61–72, 2007.
[40]
C. D. Smith, J. M. Carney, T. Tatsumo, E. R. Stadtman, R. A. Floyd, and W. R. Markesbery, “Protein oxidation in aging brain,” Annals of the New York Academy of Sciences, vol. 663, pp. 110–119, 1992.
[41]
M. A. Lovell, C. Xie, and W. R. Markesbery, “Acrolein is increased in Alzheimer's disease brain and is toxic to primary hippocampal cultures,” Neurobiology of Aging, vol. 22, no. 2, pp. 187–194, 2001.
[42]
W. R. Markesbery and M. A. Lovell, “Four-hydroxynonenal, a product of lipid peroxidation, is increased in the brain in Alzheimer's disease,” Neurobiology of Aging, vol. 19, no. 1, pp. 33–36, 1998.
[43]
A. Bierhaus and P. P. Nawroth, “Posttranslational modification of lipoproteins—a fatal attraction in metabolic disease? Commentary on: Hone et al., Alzheimer's disease amyloid-beta peptide modulates apolipoprotein E isoform specific receptor binding,” Journal of Alzheimer's Disease, vol. 7, no. 4, pp. 315–317, 2005.
[44]
P. J. Thornalley, “Protecting the genome: defence against nucleotide glycation and emerging role of glyoxalase I overexpression in multidrug resistance in cancer chemotherapy,” Biochemical Society Transactions, vol. 31, no. 6, pp. 1372–1377, 2003.
[45]
V. Srikanth, A. Maczurek, T. Phan et al., “Advanced glycation endproducts and their receptor RAGE in Alzheimer's disease,” Neurobiology of Aging, vol. 32, no. 5, pp. 763–777, 2011.
[46]
K. Horie, T. Miyata, T. Yasuda et al., “Immunohistochemical localization of advanced glycation end products, pentosidine, and carboxymethyllysine in lipofuscin pigments of Alzheimer's disease and aged neurons,” Biochemical and Biophysical Research Communications, vol. 236, no. 2, pp. 327–332, 1997.
[47]
A. Bierhaus, S. Schiekofer, M. Schwaninger et al., “Diabetes-associated sustained activation of the transcription factor nuclear factor-κB,” Diabetes, vol. 50, no. 12, pp. 2792–2808, 2001.
[48]
M. P. Mattson and S. Camandola, “NF-κB in neuronal plasticity and neurodegenerative disorders,” Journal of Clinical Investigation, vol. 107, no. 3, pp. 247–254, 2001.
[49]
O. Hori, J. Brett, T. Slattery et al., “The receptor for advanced glycation end products (RAGE) is a cellular binding site for amphoterin. Mediation of neurite outgrowth and co-expression of RAGE and amphoterin in the developing nervous system,” Journal of Biological Chemistry, vol. 270, no. 43, pp. 25752–25761, 1995.
[50]
S. D. Yan, X. Chen, J. Fu et al., “RAGE and amyloid-β peptide neurotoxicity in Alzheimer's disease,” Nature, vol. 382, no. 6593, pp. 685–691, 1996.
[51]
S. Anzilotti, C. Giampà, D. Laurenti, et al., “Immunohistochemical localization of receptor for advanced glycation end (RAGE) products in the R6/2 mouse model of Huntington's disease,” Brain Research Bulletin, vol. 87, no. 2-3, pp. 350–358, 2012.
[52]
X.-H. Li, B.-L. Lv, J.-Z. Xie, J. Liu, X.-W. Zhou, and J.-Z. Wang, “AGEs induce Alzheimer-like tau pathology and memory deficit via RAGE-mediated GSK-3 activation,” Neurobiology of Aging. In press.
[53]
Shi Du Yan, Shi Fang Yan, X. Chen et al., “Non-enzymatically glycated tau in Alzheimer's disease induces neuronal oxidant stress resulting in cytokine gene expression and release of amyloid β-peptide,” Nature Medicine, vol. 1, no. 7, pp. 693–699, 1995.
[54]
H. J. Cho, S. M. Son, S. M. Jin et al., “RAGE regulates BACE1 and Aβ generation via NFAT1 activation in Alzheimer's disease animal model,” FASEB Journal, vol. 23, no. 8, pp. 2639–2649, 2009.
[55]
L. Mucke, E. Masliah, G. Q. Yu et al., “High-level neuronal expression of Aβ(1–42) in wild-type human amyloid protein precursor transgenic mice: synaptotoxicity without plaque formation,” Journal of Neuroscience, vol. 20, no. 11, pp. 4050–4058, 2000.
[56]
O. Arancio, H. P. Zhang, X. Chen et al., “RAGE potentiates Aβ-induced perturbation of neuronal function in transgenic mice,” EMBO Journal, vol. 23, no. 20, pp. 4096–4105, 2004.
[57]
N. Origlia, M. Righi, S. Capsoni et al., “Receptor for advanced glycation end product-dependent activation of p38 mitogen-activated protein kinase contributes to amyloid-β-mediated cortical synaptic dysfunction,” Journal of Neuroscience, vol. 28, no. 13, pp. 3521–3530, 2008.
[58]
N. Origlia, O. Arancio, L. Domenici, and S. S. Yan, “MAPK, β-amyloid and synaptic dysfunction: the role of RAGE,” Expert Review of Neurotherapeutics, vol. 9, no. 11, pp. 1635–1645, 2009.
[59]
N. Origlia, S. Capsoni, A. Cattaneo et al., “Aβ-dependent inhibition of LTP in different intracortical circuits of the visual cortex: the role of RAGE,” Journal of Alzheimer's Disease, vol. 17, no. 1, pp. 59–68, 2009.
[60]
I. Vodopivec, A. Galichet, M. Knobloch, A. Bierhaus, C. W. Heizmann, and R. M. Nitsch, “RAGE does not affect amyloid pathology in transgenic arcAβ mice,” Neurodegenerative Diseases, vol. 6, no. 5-6, pp. 270–280, 2009.
[61]
B. Kuhla, C. Loske, S. Garcia De Arriba, R. Schinzel, J. Huber, and G. Münch, “Differential effects of "Advanced glycation endproducts" and β-amyloid peptide on glucose utilization and ATP levels in the neuronal cell line SH-SY5Y,” Journal of Neural Transmission, vol. 111, no. 3, pp. 427–439, 2004.
[62]
E. Cuevas, S. M. Lantz, C. Tobon-Velasco, et al., “On the in vivo early toxic properties of Aβ25–35 peptide in the rat hippocampus: involvement of the receptor-for-advanced glycation-end-products and changes in gene expression,” Neurotoxicology and Teratology, vol. 33, no. 2, pp. 288–296, 2011.
[63]
K. Takuma, F. Fang, W. Zhang et al., “RAGE-mediated signaling contributes to intraneuronal transport of amyloid-β and neuronal dysfunction,” Proceedings of the National Academy of Sciences of the United States of America, vol. 106, no. 47, pp. 20021–20026, 2009.
[64]
D. K. H. Chou, J. Zhang, F. I. Smith, P. McCaffery, and F. B. Jungalwala, “Developmental expression of receptor for advanced glycation end products (RAGE), amphoterin and sulfoglucuronyl (HNK-1) carbohydrate in mouse cerebellum and their role in neurite outgrowth and cell migration,” Journal of Neurochemistry, vol. 90, no. 6, pp. 1389–1401, 2004.
[65]
H. J. Huttunen, C. Fages, and H. Rauvala, “Receptor for advanced glycation end products (RAGE)-mediated neurite outgrowth and activation of NF-κB require the cytoplasmic domain of the receptor but different downstream signaling pathways,” Journal of Biological Chemistry, vol. 274, no. 28, pp. 19919–19924, 1999.
[66]
H. J. Huttunen, J. Kuja-Panula, and H. Rauvala, “Receptor for advanced glycation end products (RAGE) signaling induces CREB-dependent chromogranin expression during neuronal differentiation,” Journal of Biological Chemistry, vol. 277, no. 41, pp. 38635–38646, 2002.
[67]
H. J. Huttunen, J. Kuja-Panula, G. Sorci, A. L. Agneletti, R. Donato, and H. Rauvala, “Coregulation of neurite outgrowth and cell survival by amphoterin and S100 proteins through receptor for advanced glycation end products (RAGE) activation,” Journal of Biological Chemistry, vol. 275, no. 51, pp. 40096–40105, 2000.
[68]
G. Sajithlal, H. Huttunen, H. Rauvala, and G. Münch, “Receptor for advanced glycation end products plays a more important role in cellular survival than in neurite outgrowth during retinoic acid-induced differentiation of neuroblastoma cells,” Journal of Biological Chemistry, vol. 277, no. 9, pp. 6888–6897, 2002.
[69]
G. Srikrishna, H. J. Huttunen, L. Johansson et al., “N-glycans on the receptor for advanced glycation end products influence amphoterin binding and neurite outgrowth,” Journal of Neurochemistry, vol. 80, no. 6, pp. 998–1008, 2002.
[70]
L. R. Ling, W. Trojaborg, W. Qu et al., “Antagonism of RAGE suppresses peripheral nerve regeneration,” FASEB Journal, vol. 18, no. 15, pp. 1812–1817, 2004.
[71]
L. L. Rong, S. F. Yan, T. Wendt, et al., “RAGE modulates peripheral nerve regeneration via recruitment of both inflammatory and axonal outgrowth pathways,” FASEB Journal, vol. 18, no. 15, pp. 1818–1825, 2004.
[72]
S. Fuller, M. Steele, and G. Münch, “Activated astroglia during chronic inflammation in Alzheimer's disease-do they neglect their neurosupportive roles?” Mutation Research, vol. 690, no. 1-2, pp. 40–49, 2010.
[73]
I. Blasko, M. Stampfer-Kountchev, P. Robatscher, R. Veerhuis, P. Eikelenboom, and B. Grubeck-Loebenstein, “How chronic inflammation can affect the brain and support the development of Alzheimer's disease in old age: the role of microglia and astrocytes,” Aging Cell, vol. 3, no. 4, pp. 169–176, 2004.
[74]
S. C. Weninger and B. A. Yankner, “Inflammation and Alzheimer disease: the good, the bad, and the ugly,” Nature Medicine, vol. 7, no. 5, pp. 527–528, 2001.
[75]
A. Bierhaus, D. M. Stern, and P. P. Nawroth, “RAGE in inflammation: a new therapeutic target?” Current Opinion in Investigational Drugs, vol. 7, no. 11, pp. 985–991, 2008.
[76]
A. K. Mohamed, A. Bierhaus, S. Schiekofer, H. Tritschler, R. Ziegler, and P. P. Nawroth, “The role of oxidative stress and NF-κB activation in late diabetic complications,” BioFactors, vol. 10, no. 2-3, pp. 157–167, 1999.
[77]
S. D. Yan, H. Zhu, J. Fu et al., “Amyloid-β peptide-receptor for advanced glycation endproduct interaction elicits neuronal expression of macrophage-colony stimulating factor: a proinflammatory pathway in Alzheimer disease,” Proceedings of the National Academy of Sciences of the United States of America, vol. 94, no. 10, pp. 5296–5301, 1997.
[78]
Fang, L. F. Lue, S. Yan et al., “RAGE-dependent signaling in microglia contributes to neuroinflammation, Aβ accumulation, and impaired learning/memory in a mouse model of Alzheimer's disease,” FASEB Journal, vol. 24, no. 4, pp. 1043–1055, 2010.
[79]
N. Origlia, C. Bonadonna, A. Rosellini et al., “Microglial receptor for advanced glycation end product-dependent signal pathway drives β-amyloid-induced synaptic depression and long-term depression impairment in entorhinal cortex,” Journal of Neuroscience, vol. 30, no. 34, pp. 11414–11425, 2010.
[80]
B. S. Desai, J. A. Schneider, J. L. Li, P. M. Carvey, and B. Hendey, “Evidence of angiogenic vessels in Alzheimer's disease,” Journal of Neural Transmission, vol. 116, no. 5, pp. 587–597, 2009.
[81]
M. Ujiie, D. L. Dickstein, D. A. Carlow, and W. A. Jefferies, “Blood-brain barrier permeability precedes senile plaque formation in an Alzheimer disease model,” Microcirculation, vol. 10, no. 6, pp. 463–470, 2003.
[82]
A. J. Farrall and J. M. Wardlaw, “Blood-brain barrier: ageing and microvascular disease—systematic review and meta-analysis,” Neurobiology of Aging, vol. 30, no. 3, pp. 337–352, 2009.
[83]
T. Malm, M. Koistinaho, A. Muona, J. Magga, and J. Koistinaho, “The role and therapeutic potential of monocytic cells in Alzheimer's disease,” GLIA, vol. 58, no. 8, pp. 889–900, 2010.
[84]
R. Giri, S. Selvaraj, C. A. Miller et al., “Effect of endothelial cell polarity on β-amyloid-induced migration of monocytes across normal and AD endothelium,” American Journal of Physiology, vol. 283, no. 3, pp. C895–C904, 2002.
[85]
G. S. Watson and S. Craft, “Insulin resistance, inflammation, and cognition in Alzheimer's Disease: lessons for multiple sclerosis,” Journal of the Neurological Sciences, vol. 245, no. 1-2, pp. 21–33, 2006.
[86]
Y. D. Ke, F. Delerue, A. Gladbach, J. G？tz, and L. M. Ittner, “Experimental diabetes mellitus exacerbates Tau pathology in a transgenic mouse model of Alzheimer's disease,” PLoS ONE, vol. 4, no. 11, article e7917, 2009.
[87]
F. Turturro, E. Friday, and T. Welbourne, “Hyperglycemia regulates thioredoxin-ROS activity through induction of thioredoxin-interacting protein (TXNIP) in metastatic breast cancer-derived cells MDA-MB-231,” BMC Cancer, vol. 7, article 96, 2007.
[88]
D. M. Muoio, “TXNIP links redox circuitry to glucose control,” Cell Metabolism, vol. 5, no. 6, pp. 412–414, 2007.
[89]
H. Parikh, E. Carlsson, W. A. Chutkow et al., “TXNIP regulates peripheral glucose metabolism in humans,” PLoS Medicine, vol. 4, no. 5, article e158, 2007.
[90]
S. A. Mousa, C. Gallati, T. Simone et al., “Dual targeting of the antagonistic pathways mediated by Sirt1 and TXNIP as a putative approach to enhance the efficacy of anti-aging interventions,” Aging, vol. 1, no. 4, pp. 412–424, 2009.
[91]
C. Blouet and G. J. Schwartz, “Nutrient-sensing hypothalamic TXNIP links nutrient excess to energy imbalance in mice,” Journal of Neuroscience, vol. 31, no. 16, pp. 6019–6027, 2011.
[92]
M. C. Levendusky, J. Basle, S. Chang, N. V. Mandalaywala, J. M. Voigt, and R. E. Dearborn Jr., “Expression and regulation of vitamin D3 upregulated protein 1 (VDUP1) is conserved in mammalian and insect brain,” Journal of Comparative Neurology, vol. 517, no. 5, pp. 581–600, 2009.
[93]
T. Saitoh, S. Tanaka, and T. Koike, “Rapid induction and Ca2+ influx-mediated suppression of vitamin D3 up-regulated protein 1 (VDUP1) mRNA in cerebellar granule neurons undergoing apoptosis,” Journal of Neurochemistry, vol. 78, no. 6, pp. 1267–1276, 2001.
[94]
S. Papadia, F. X. Soriano, F. Léveillé et al., “Synaptic NMDA receptor activity boosts intrinsic antioxidant defenses,” Nature Neuroscience, vol. 11, no. 4, pp. 476–487, 2008.
[95]
H. Decker, S. Jürgensen, M. F. Adrover et al., “N-Methyl-d-aspartate receptors are required for synaptic targeting of Alzheimer's toxic amyloid-β peptide oligomers,” Journal of Neurochemistry, vol. 115, no. 6, pp. 1520–1529, 2010.
[96]
H. Oakley, S. L. Cole, S. Logan et al., “Intraneuronal β-amyloid aggregates, neurodegeneration, and neuron loss in transgenic mice with five familial Alzheimer's disease mutations: potential factors in amyloid plaque formation,” Journal of Neuroscience, vol. 26, no. 40, pp. 10129–10140, 2006.
[97]
A. Faria, D. Pestana, D. Teixeira et al., “Flavonoid transport across RBE4 cells: a blood-brain barrier model,” Cellular and Molecular Biology Letters, vol. 15, no. 2, pp. 234–241, 2010.
[98]
L. Perrone, G. Peluso, and M. A. B. Melone, “RAGE recycles at the plasma membrane in S100B secretory vesicles and promotes Schwann cells morphological changes,” Journal of Cellular Physiology, vol. 217, no. 1, pp. 60–71, 2008.
[99]
C. World, O. N. Spindel, and B. C. Berk, “Thioredoxin-interacting protein mediates TRX1 translocation to the plasma membrane in response to tumor necrosis factor-α: a key mechanism for vascular endothelial growth factor receptor-2 transactivation by reactive oxygen species,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 31, no. 8, pp. 1890–1897, 2011.
[100]
F. Xiong, S. Leonov, A. C. Howard et al., “Receptor for Advanced Glycation End products (RAGE) prevents endothelial cell membrane resealing and regulates F-actin remodeling in a β-catenin-dependent manner,” Journal of Biological Chemistry, vol. 286, no. 40, pp. 35061–35070, 2011.
[101]
M. N. Sabbagh, A. Agro, J. Bell, P. S. Aisen, E. Schweizer, and D. Galasko, “PF-04494700, an oral inhibitor of receptor for advanced glycation end products (RAGE), in Alzheimer disease,” Alzheimer Disease & Associated Disorders, vol. 25, no. 3, pp. 206–212, 2011.
[102]
A. Cassese, I. Esposito, F. Fiory et al., “In skeletal muscle advanced glycation end products (AGEs) inhibit insulin action and induce the formation of multimolecular complexes including the receptor for AGEs,” Journal of Biological Chemistry, vol. 283, no. 52, pp. 36088–36099, 2008.
[103]
T. B. Koenen, R. Stienstra, L. J. Van Tits et al., “Hyperglycemia activates caspase-1 and TXNIP-mediated IL-1β transcription in human adipose tissue,” Diabetes, vol. 60, no. 2, pp. 517–524, 2011.
