Epidemiological studies suggest that being obese in midlife is a risk factor for cognitive decline and dementia in later life. Hyperinsulinemia is one of the most frequent endocrine features in overweight people which results in insulin desensitization. Thus, chronically high insulin levels have been identified as risk factor for dementia. Accordingly, chronically high insulin levels might be harmful for brain function. Furthermore, insulin and IGF-1-induced signaling is reduced in the brains of patients suffering from Alzheimer’s disease (AD). Interestingly, studies in rodents suggest that reduced insulin receptor (IR) and insulin-like growth factor-1 receptor (IGF-1R) signaling decrease AD pathology, that is, β-amyloid toxicity. Data obtained in C. elegans indicate that the beneficial effect mediated via reduced IR/IGF-1R signaling might partially be induced via the forkhead-box O transcription factors (FoxO). In the mammalian brain, there are FoxO1, FoxO3a, and FoxO6 expressed. Surprisingly, high-fat diet specifically reduces the expression of FoxO3a and FoxO6 suggesting that IR/IGF-1 → FoxO-mediated transcription is involved in the pathogenesis of obesity-associated cognitive impairment. Therefore, the function of FoxO1 and FoxO3a has been investigated in animal models of Alzheimer’s disease in detail. The current paper focuses on the role of IR/IGF-1 signaling and IR/IGF-1 → FoxO-mediated transcription for the pathogenesis of obesity-associated dementia. 1. Introduction Obesity is characterized by a body mass index (BMI) of over 30？kg/m2. The prevalence of obesity will rise to approximately 700 million people worldwide in 2015 [1]. Furthermore, midlife overweight and obesity might increase the risk for dementia during aging [2–4]. Hence, the role of obesity or overweight status in the development of cognitive decline or dementia is a major health concern and possibly associated with enormous health care costs. Prospective investigations on the role of BMI for the development of dementia did not provide a conclusive picture, yet. Some studies report no association or even decreased BMI to be associated with dementia or Alzheimer’s disease [5, 6], and others suggested higher BMI to be a risk factor for dementia [7] or that overweight in middle age is associated with dementia decades later [8, 9]. It seems to be difficult to estimate the exact role of obesity itself for the initiation or progress of cognitive impairment. Furthermore, obesity is associated with a variety of cardiovascular risk factors influencing long-term cognitive performance.
References
[1]
World Health Organization, Controlling the global obesity epidemic, 2011, http://www.who.int/nutrition/topics/obesity/en/index.html.
[2]
L. B. Hassing, A. K. Dahl, V. Thorvaldsson et al., “Overweight in midlife and risk of dementia: a 40-year follow-up study,” International Journal of Obesity, vol. 33, no. 8, pp. 893–898, 2009.
[3]
J. A. Luchsinger, B. Patel, M. X. Tang, N. Schupf, and R. Mayeux, “Measures of adiposity and dementia risk in elderly persons,” Archives of Neurology, vol. 64, no. 3, pp. 392–398, 2007.
[4]
W. L. Xu, A. R. Atti, M. Gatz, N. L. Pedersen, B. Johansson, and L. Fratiglioni, “Midlife overweight and obesity increase late-life dementia risk: a population-based twin study,” Neurology, vol. 76, no. 18, pp. 1568–1574, 2011.
[5]
F. Nourhashémi, V. Deschamps, S. Larrieu, L. Letenneur, J. F. Dartigues, and P. Barberger-Gateau, “Body mass index and incidence of dementia: the PAQUID study,” Neurology, vol. 60, no. 1, pp. 117–119, 2003.
[6]
R. Stewart, K. Masaki, Q. L. Xue et al., “A 32-year prospective study of change in body weight and incident dementia: the Honolulu-Asia Aging Study,” Archives of Neurology, vol. 62, no. 1, pp. 55–60, 2005.
[7]
D. Gustafson, E. Rothenberg, K. Blennow, B. Steen, and I. Skoog, “An 18-year follow-up of overweight and risk of Alzheimer disease,” Archives of Internal Medicine, vol. 163, no. 13, pp. 1524–1528, 2003.
[8]
M. Kivipelto, T. Ngandu, L. Fratiglioni et al., “Obesity and vascular risk factors at midlife and the risk of dementia and Alzheimer disease,” Archives of Neurology, vol. 62, no. 10, pp. 1556–1560, 2005.
[9]
R. A. Whitmer, E. P. Gunderson, E. Barrett-Connor, C. P. Quesenberry, and K. Yaffe, “Obesity in middle age and future risk of dementia: a 27 year longitudinal population based study,” British Medical Journal, vol. 330, no. 7504, pp. 1360–1362, 2005.
[10]
M. F. Elias, et al., “Cognitive functioning and dementia: back to the future,” Journal Alzheimers Disease. In press.
[11]
A. Dahl, L. B. Hassing, E. Fransson et al., “Being overweight in midlife is associated with lower cognitive ability and steeper cognitive decline in late life,” Journals of Gerontology—Series A, vol. 65, no. 1, pp. 57–62, 2010.
[12]
V. S. Laitala, J. Kaprio, M. Koskenvuo, I. R？ih？, J. O. Rinne, and K. Silventoinen, “Association and causal relationship of midlife obesity and related metabolic disorders with old age cognition,” Current Alzheimer Research, vol. 8, no. 6, pp. 699–706, 2011.
[13]
M. Wakisaka, S. Nagamachi, K. Inoue, Y. Morotomi, K. Nunoi, and M. Fujishima, “Reduced regional cerebral blood flow in aged noninsulin-dependent diabetic patients with no history of cerebrovascular disease: evaluation by N-lsopropyl-123I-p-iodoamphetamine with single-photon emission computed tomography,” Journal of Diabetic Complications, vol. 4, no. 4, pp. 170–174, 1990.
[14]
J. Jakobsen, M. Nedergaard, M. Aarslew-Jensen, and N. H. Diemer, “Regional brain glucose metabolism and blood flow in streptozocin-induced diabetic rats,” Diabetes, vol. 39, no. 4, pp. 437–440, 1990.
[15]
C. Benedict, M. Hallschmid, A. Hatke et al., “Intranasal insulin improves memory in humans,” Psychoneuroendocrinology, vol. 29, no. 10, pp. 1326–1334, 2004.
[16]
M. Van Oijen, O. I. Okereke, J. H. Kang et al., “Fasting insulin levels and cognitive decline in older women without diabetes,” Neuroepidemiology, vol. 30, no. 3, pp. 174–179, 2008.
[17]
O. I. Okereke, T. Kurth, M. N. Pollak, J. M. Gaziano, and F. Grodstein, “Fasting plasma insulin, c-peptide and cognitive change in older men without diabetes: results from the physicians' health study ii,” Neuroepidemiology, vol. 34, no. 4, pp. 200–207, 2010.
[18]
J. Havrankova, J. Roth, and M. Brownstein, “Insulin receptors are widely distributed in the central nervous system of the rat,” Nature, vol. 272, no. 5656, pp. 827–829, 1978.
[19]
I. Jialal, G. L. King, and S. Buchwald, “Processing of insulin by bovine endothelial cells in culture. Internalization without degradation,” Diabetes, vol. 33, no. 8, pp. 794–800, 1984.
[20]
G. L. King and S. M. Johnson, “Receptor-mediated transport of insulin across endothelial cells,” Science, vol. 227, no. 4694, pp. 1583–1586, 1985.
[21]
M. Van Houten and B. I. Posner, “Insulin binds to brain blood vessels in vivo,” Nature, vol. 282, no. 5739, pp. 623–625, 1979.
[22]
J. M. Hill, M. A. Lesniak, C. B. Pert, and J. Roth, “Autoradiographic localization of insulin receptors in rat brain: prominence in olfactory and limbic areas,” Neuroscience, vol. 17, no. 4, pp. 1127–1138, 1986.
[23]
D. G. Baskin, D. Davidson, and E. S. Corp, “An inexpensive microcomputer digital imaging system for densitometry: quantitative autoradiography of insulin receptors with 125I and LKB Ultrofilm,” Journal of Neuroscience Methods, vol. 16, no. 2, pp. 119–129, 1986.
[24]
M. Van Houten, D. M. Nance, S. Gauthier, and B. I. Posner, “Origin of insulin-receptive nerve terminals in rat median eminence,” Endocrinology, vol. 113, no. 4, pp. 1393–1399, 1983.
[25]
G. A. Werther, A. Hogg, B. J. Oldfield et al., “Localization and characterization of insulin receptors in rat brain and pituitary gland using in vitro autoradiography and computerized densitometry,” Endocrinology, vol. 121, no. 4, pp. 1562–1570, 1987.
[26]
J. Unger, T. H. McNeill, R. T. Moxley, M. White, A. Moss, and J. N. Livingston, “Distribution of insulin receptor-like immunoreactivity in the rat forebrain,” Neuroscience, vol. 31, no. 1, pp. 143–157, 1989.
[27]
C. K. Chou, T. J. Dull, and D. S. Russell, “Human insulin receptors mutated at the ATP-binding site lack protein tyrosine kinase activity and fail to mediate postreceptor effects of insulin,” The Journal of Biological Chemistry, vol. 262, no. 4, pp. 1842–1847, 1987.
[28]
A. Ullrich, A. Gray, A. W. Tam et al., “Insulin-like growth factor I receptor primary structure: comparison with insulin receptor suggests structural determinants that define functional specificity,” The EMBO Journal, vol. 5, no. 10, pp. 2503–2512, 1986.
[29]
E. Van Obberghen, M. Kasuga, and A. Le Cam, “Biosynthetic labeling of insulin receptor: studies of subunits in cultured human IM-9 lymphocytes,” Proceedings of the National Academy of Sciences of the United States of America, vol. 78, no. 2, pp. 1052–1056, 1981.
[30]
B. E. Lavan, V. R. Fantin, E. T. Chang, W. S. Lane, S. R. Keller, and G. E. Lienhard, “A novel 160-kDa phosphotyrosine protein in insulin-treated embryonic kidney cells is a new member of the insulin receptor substrate family,” The Journal of Biological Chemistry, vol. 272, no. 34, pp. 21403–21407, 1997.
[31]
B. E. Lavan, W. S. Lane, and G. E. Lienhard, “The 60-kDa phosphotyrosine protein in insulin-treated adipocytes is a new member of the insulin receptor substrate family,” The Journal of Biological Chemistry, vol. 272, no. 17, pp. 11439–11443, 1997.
[32]
X. J. Sun, P. Rothenberg, C. R. Kahn et al., “Structure of the insulin receptor substrate IRS-1 defines a unique signal transduction protein,” Nature, vol. 352, no. 6330, pp. 73–77, 1991.
[33]
L. Yenush and M. F. White, “The IRS-signalling system during insulin and cytokine action,” BioEssays, vol. 19, no. 6, pp. 491–500, 1997.
[34]
B. Cheatham and C. R. Kahn, “Insulin action and the insulin signaling network,” Endocrine Reviews, vol. 16, no. 2, pp. 117–142, 1995.
[35]
D. A. Fruman, L. E. Rameh, and L. C. Cantley, “Phosphoinositide binding domains: embracing 3-phosphate,” Cell, vol. 97, no. 7, pp. 817–820, 1999.
[36]
M. F. White, “IRS proteins and the common path to diabetes,” American Journal of Physiology, vol. 283, no. 3, pp. E413–E422, 2002.
[37]
P. Gual, Y. Le Marchand-Brustel, and J. F. Tanti, “Positive and negative regulation of insulin signaling through IRS-1 phosphorylation,” Biochimie, vol. 87, no. 1, pp. 99–109, 2005.
[38]
C. Weigert, A. M. Hennige, T. Brischmann et al., “The phosphorylation of Ser318 of insulin receptor substrate 1 is not per se inhibitory in skeletal muscle cells but is necessary to trigger the attenuation of the insulin-stimulated signal,” The Journal of Biological Chemistry, vol. 280, no. 45, pp. 37393–37399, 2005.
[39]
C. Weigert, M. Kron, H. Kalbacher et al., “Interplay and effects of temporal changes in the phosphorylation state of serine-302, -307, and -318 of insulin receptor substrate-1 on insulin action in skeletal muscle cells,” Molecular Endocrinology, vol. 22, no. 12, pp. 2729–2740, 2008.
[40]
B. Vanhaesebroeck, K. Ali, A. Bilancio, B. Geering, and L. C. Foukas, “Signalling by PI3K isoforms: insights from gene-targeted mice,” Trends in Biochemical Sciences, vol. 30, no. 4, pp. 194–204, 2005.
[41]
D. A. Fruman, R. E. Meyers, and L. C. Cantley, “Phosphoinositide kinases,” Annual Review of Biochemistry, vol. 67, pp. 481–507, 1998.
[42]
D. R. Alessi, M. Andjelkovic, B. Caudwell et al., “Mechanism of activation of protein kinase B by insulin and IGF-1,” The EMBO Journal, vol. 15, no. 23, pp. 6541–6551, 1996.
[43]
M. A. Lawlor and D. R. Alessi, “PKB/Akt: a key mediator of cell proliferation, survival and insulin responses?” Journal of Cell Science, vol. 114, part 16, pp. 2903–2910, 2001.
[44]
D. Stokoe, L. R. Stephens, T. Copeland et al., “Dual role of phosphatidylinositol-3,4,5-trisphosphate in the activation of protein kinase B,” Science, vol. 277, no. 5325, pp. 567–570, 1997.
[45]
R. C. Hresko, H. Murata, and M. Mueckler, “Phosphoinositide-dependent kinase-2 is a distinct protein kinase in a novel cytoskeletal fraction associated with adipocyte plasma membranes,” The Journal of Biological Chemistry, vol. 278, no. 24, pp. 21615–21622, 2003.
[46]
W. Kolch, “Meaningful relationships: the regulation of the Ras/Raf/MEK/ERK pathway by protein interactions,” Biochemical Journal, vol. 351, part 2, pp. 289–305, 2000.
[47]
J. David Sweatt, “The neuronal MAP kinase cascade: a biochemical signal integration system subserving synaptic plasticity and memory,” Journal of Neurochemistry, vol. 76, no. 1, pp. 1–10, 2001.
[48]
T. Furuyama, T. Nakazawa, I. Nakano, and N. Mori, “Identification of the differential distribution patterns of mRNAs and consensus binding sequences for mouse DAF-16 homologues,” Biochemical Journal, vol. 349, no. 2, pp. 629–634, 2000.
[49]
F. M. J. Jacobs, L. P. Van der Heide, P. J. E. C. Wijchers, J. P. H. Burbach, M. F. M. Hoekman, and M. P. Smidt, “FoxO6, a novel member of the FoxO class of transcription factors with distinct shuttling dynamics,” The Journal of Biological Chemistry, vol. 278, no. 38, pp. 35959–35967, 2003.
[50]
M. F. M. Hoekman, F. M. J. Jacobs, M. P. Smidt, and J. P. H. Burbach, “Spatial and temporal expression of FoxO transcription factors in the developing and adult murine brain,” Gene Expression Patterns, vol. 6, no. 2, pp. 134–140, 2006.
[51]
J. Zemva, K. Schilbach, O. St？hr et al., “Central FoxO3a and FoxO6 expression is downregulated in obesity induced diabetes but not in aging,” Experimental and Clinical Endocrinology and Diabetes. In press.
[52]
L. Partridge and J. C. Brüning, “Forkhead transcription factors and ageing,” Oncogene, vol. 27, no. 16, pp. 2351–2363, 2008.
[53]
W. H. Biggs, J. Meisenhelder, T. Hunter, W. K. Cavenee, and K. C. Arden, “Protein kinase B/Akt-mediated phosphorylation promotes nuclear exclusion of the winged helix transcription factor FKHR1,” Proceedings of the National Academy of Sciences of the United States of America, vol. 96, no. 13, pp. 7421–7426, 1999.
[54]
J. Gilley, P. J. Coffer, and J. Ham, “FOXO transcription factors directly activate bim gene expression and promote apoptosis in sympathetic neurons,” Journal of Cell Biology, vol. 162, no. 4, pp. 613–622, 2003.
[55]
P. F. Dijkers, R. H. Medema, C. Pals et al., “Forkhead transcription factor FKHR-L1 modulates cytokine-dependent transcriptional regulation of p27KIP1,” Molecular and Cellular Biology, vol. 20, no. 24, pp. 9138–9148, 2000.
[56]
R. H. Medema, G. J. P. L. Kops, J. L. Bos, and B. M. T. Burgering, “AFX-like Forkhead transcription factors mediate cell-cycle regulation by Ras and PKB through p27(kip1),” Nature, vol. 404, no. 6779, pp. 782–787, 2000.
[57]
G. J. P. L. Kops, T. B. Dansen, P. E. Polderman et al., “Forkhead transcription factor FOXO3a protects quiescent cells from oxidative stress,” Nature, vol. 419, no. 6904, pp. 316–321, 2002.
[58]
K. E. Van Der Vos and P. J. Coffer, “The extending network of FOXO transcriptional target genes,” Antioxidants and Redox Signaling, vol. 14, no. 4, pp. 579–592, 2011.
[59]
A. Brunet, A. Bonni, M. J. Zigmond et al., “Akt promotes cell survival by phosphorylating and inhibiting a forkhead transcription factor,” Cell, vol. 96, no. 6, pp. 857–868, 1999.
[60]
G. J. P. L. Kops, N. D. De Ruiter, A. M. M. De Vries-Smits, D. R. Powell, J. L. Bos, and B. M. T. Burgering, “Direct control of the forkhead transcription faotor AFX by protein kinase B,” Nature, vol. 398, no. 6728, pp. 630–634, 1999.
[61]
G. Rena, G. Shaodong, S. C. Cichy, T. G. Unterman, and P. Cohen, “Phosphorylation of the transcription factor forkhead family member FKHR by protein kinase B,” The Journal of Biological Chemistry, vol. 274, no. 24, pp. 17179–17183, 1999.
[62]
E. D. Tang, G. Nu？ez, F. G. Barr, and K. L. Guan, “Negative regulation of the forkhead transcription factor FKHR by Akt,” The Journal of Biological Chemistry, vol. 274, no. 24, pp. 16741–16746, 1999.
[63]
A. Brunet, D. Roux, P. Lenormand, S. Dowd, S. Keyse, and J. Pouysségur, “Nuclear translocation of p42/p44 mitogen-activated protein kinase is required for growth factor-induced gene expression and cell cycle entry,” The EMBO Journal, vol. 18, no. 3, pp. 664–674, 1999.
[64]
H. Huang and D. J. Tindall, “Dynamic FoxO transcription factors,” Journal of Cell Science, vol. 120, no. 15, pp. 2479–2487, 2007.
[65]
W. Fu, Q. Ma, L. Chen et al., “MDM2 acts downstream of p53 as an E3 ligase to promote FOXO ubiquitination and degradation,” The Journal of Biological Chemistry, vol. 284, no. 21, pp. 13987–14000, 2009.
[66]
H. Huang, K. M. Regan, F. Wang et al., “Skp2 inhibits FOXO1 in tumor suppression through ubiquitin-mediated degradation,” Proceedings of the National Academy of Sciences of the United States of America, vol. 102, no. 5, pp. 1649–1654, 2005.
[67]
J. Y. Yang, C. S. Zong, W. Xia et al., “ERK promotes tumorigenesis by inhibiting FOXO3a via MDM2-mediated degradation,” Nature Cell Biology, vol. 10, no. 2, pp. 138–148, 2008.
[68]
W. Yang, N. G. Dolloff, and W. S. El-Deiry, “ERK and MDM2 prey on FOXO3a,” Nature Cell Biology, vol. 10, no. 2, pp. 125–126, 2008.
[69]
A. van der Horst, A. M. M. de Vries-Smits, A. B. Brenkman et al., “FOXO4 transcriptional activity is regulated by monoubiquitination and USP7/HAUSP,” Nature Cell Biology, vol. 8, no. 10, pp. 1064–1073, 2006.
[70]
K. Yamagata, H. Daitoku, Y. Takahashi et al., “Arginine methylation of FOXO transcription factors inhibits their phosphorylation by Akt,” Molecular Cell, vol. 32, no. 2, pp. 221–231, 2008.
[71]
M. Li, J. Luo, C. L. Brooks, and W. Gu, “Acetylation of p53 inhibits its ubiquitination by Mdm2,” The Journal of Biological Chemistry, vol. 277, no. 52, pp. 50607–50611, 2002.
[72]
H. Daitoku, M. Hatta, H. Matsuzaki et al., “Silent information regulator 2 potentiates Foxo 1-mediated transcription through its deacetylase activity,” Proceedings of the National Academy of Sciences of the United States of America, vol. 101, no. 27, pp. 10042–10047, 2004.
[73]
H. Matsuzaki, H. Daitoku, M. Hatta, H. Aoyama, K. Yoshimochi, and A. Fukamizu, “Acetylation of Foxo1 alters its DNA-binding ability and sensitivity to phosphorylation,” Proceedings of the National Academy of Sciences of the United States of America, vol. 102, no. 32, pp. 11278–11283, 2005.
[74]
A. Brunet, L. B. Sweeney, J. F. Sturgill et al., “Stress-dependent regulation of FOXO transcription factors by the SIRT1 deacetylase,” Science, vol. 303, no. 5666, pp. 2011–2015, 2004.
[75]
Y. I. Kitamura, T. Kitamura, J. P. Kruse et al., “FoxO1 protects against pancreatic β cell failure through NeuroD and MafA induction,” Cell Metabolism, vol. 2, no. 3, pp. 153–163, 2005.
[76]
A. Besson, S. F. Dowdy, and J. M. Roberts, “CDK inhibitors: cell cycle regulators and beyond,” Developmental Cell, vol. 14, no. 2, pp. 159–169, 2008.
[77]
E. E. Irvine, L. Drinkwater, K. Radwanska et al., “Insulin receptor substrate 2 is a negative regulator of memory formation,” Learning and Memory, vol. 18, no. 6, pp. 375–383, 2011.
[78]
M. Citron, “Alzheimer's disease: treatments in discovery and development,” Nature Neuroscience, vol. 5, supplement, pp. 1055–1057, 2002.
[79]
A. R. Cole, A. Astell, C. Green, and C. Sutherland, “Molecular connexions between dementia and diabetes,” Neuroscience and Biobehavioral Reviews, vol. 31, no. 7, pp. 1046–1063, 2007.
[80]
C. L. Masters, G. Simms, and N. A. Weinman, “Amyloid plaque core protein in Alzheimer disease and Down syndrome,” Proceedings of the National Academy of Sciences of the United States of America, vol. 82, no. 12, pp. 4245–4249, 1985.
[81]
C. A. Ross and M. A. Poirier, “What is the role of protein aggregation in neurodegeneration?” Nature Reviews Molecular Cell Biology, vol. 6, no. 11, pp. 891–898, 2005.
[82]
L. Fr？lich, D. Blum-Degen, H. G. Bernstein et al., “Brain insulin and insulin receptors in aging and sporadic Alzheimer's disease,” Journal of Neural Transmission, vol. 105, no. 4-5, pp. 423–438, 1998.
[83]
L. Fr？lich, D. Blum-Degen, P. Riederer, and S. Hoyer, “A disturbance in the neuronal insulin receptor signal transduction in sporadic Alzheimer's disease,” Annals of the New York Academy of Sciences, vol. 893, pp. 290–293, 1999.
[84]
A. M. Moloney, R. J. Griffin, S. Timmons, R. O'Connor, R. Ravid, and C. O'Neill, “Defects in IGF-1 receptor, insulin receptor and IRS-1/2 in Alzheimer's disease indicate possible resistance to IGF-1 and insulin signalling,” Neurobiology of Aging, vol. 31, no. 2, pp. 224–243, 2010.
[85]
E. J. Rivera, A. Goldin, N. Fulmer, R. Tavares, J. R. Wands, and S. M. De La Monte, “Insulin and insulin-like growth factor expression and function deteriorate with progression of Alzheimer's disease: link to brain reductions in acetylcholine,” Journal of Alzheimer's Disease, vol. 8, no. 3, pp. 247–268, 2005.
[86]
E. R. L. C. Vardy, P. J. Rice, P. C. W. Bowie, J. D. Holmes, P. J. Grant, and N. M. Hooper, “Increased circulating insulin-like growth factor-1 in late-onset Alzheimer's disease,” Journal of Alzheimer's Disease, vol. 12, no. 4, pp. 285–290, 2007.
[87]
H. Pilcher, “Alzheimer's disease could be ‘type 3 diabetes’,” The The Lancet Neurology, vol. 5, no. 5, pp. 388–389, 2006.
[88]
N. Hirokawa, T. Funakoshi, R. Sato-Harada, and Y. Kanai, “Selective stabilization of tau in axons and microtubule-associated protein 2C in cell bodies and dendrites contributes to polarized localization of cytoskeletal proteins in mature neurons,” Journal of Cell Biology, vol. 132, no. 4, pp. 667–679, 1996.
[89]
L. M. Ittner, Y. D. Ke, F. Delerue et al., “Dendritic function of tau mediates amyloid-β toxicity in alzheimer's disease mouse models,” Cell, vol. 142, no. 3, pp. 387–397, 2010.
[90]
J. G？tz, L. M. Ittner, and S. Kins, “Do axonal defects in tau and amyloid precursor protein transgenic animals model axonopathy in Alzheimer's disease?” Journal of Neurochemistry, vol. 98, no. 4, pp. 993–1006, 2006.
[91]
E. Sontag, V. Nunbhakdi-Craig, G. Lee, G. S. Bloom, and M. C. Mumby, “Regulation of the phosphorylation state and microtubule-binding activity of tau by protein phosphatase 2A,” Neuron, vol. 17, no. 6, pp. 1201–1207, 1996.
[92]
R. Liu, X. W. Zhou, H. Tanila et al., “Phosphorylated PP2A (tyrosine 307) is associated with Alzheimer neurofibrillary pathology: in Focus,” Journal of Cellular and Molecular Medicine, vol. 12, no. 1, pp. 241–257, 2008.
[93]
D. Goldgaber, M. I. Lerman, and O. W. McBride, “Characterization and chromosomal localization of a cDNA encodingbrain amyloid of Alzheimer's disease,” Science, vol. 235, no. 4791, pp. 877–880, 1987.
[94]
J. Kang, H. G. Lemaire, and A. Unterbeck, “The precursor of Alzheimer's disease amyloid A4 protein resembles a cell-surface receptor,” Nature, vol. 325, no. 6106, pp. 733–736, 1987.
[95]
N. K. Robakis, H. M. Wisniewski, and E. C. Jenkins, “Chromosome 21q21 sublocalisation of gene endocing beta-amyloid peptide in cerebral vessels and neuritic (senile) plaques of people with Alzheimer disease and Down syndrome,” The Lancet, vol. 1, no. 8529, pp. 384–385, 1987.
[96]
R. E. Tanzi, J. F. Gusella, and P. C. Watkins, “Amyloid β protein gene: cDNA, mRNA distribution, and genetic linkage near the Alzheimer locus,” Science, vol. 235, no. 4791, pp. 880–884, 1987.
[97]
A. Rovelet-Lecrux, D. Hannequin, G. Raux et al., “APP locus duplication causes autosomal dominant early-onset Alzheimer disease with cerebral amyloid angiopathy,” Nature Genetics, vol. 38, no. 1, pp. 24–26, 2006.
[98]
K. Sleegers, N. Brouwers, I. Gijselinck et al., “APP duplication is sufficient to cause early onset Alzheimer's dementia with cerebral amyloid angiopathy,” Brain, vol. 129, no. 11, pp. 2977–2983, 2006.
[99]
L. Bertram and R. E. Tanzi, “The genetic epidemiology of neurodegenerative disease,” The Journal of Clinical Investigation, vol. 115, no. 6, pp. 1449–1457, 2005.
[100]
E. I. Rogaev, R. Sherrington, E. A. Rogaeva et al., “Familial Alzheimer's disease in kindreds with missense mutations in a gene on chromosome 1 related to the Alzheimer's disease type 3 gene,” Nature, vol. 376, no. 6543, pp. 775–778, 1995.
[101]
G. D. Schellenberg, T. D. Bird, E. M. Wijsman et al., “Genetic linkage evidence for a familial Alzheimer's disease locus on chromosome 14,” Science, vol. 258, no. 5082, pp. 668–671, 1992.
[102]
R. Sherrington, S. Froelich, S. Sorbi et al., “Alzheimer's disease associated with mutations in presenilin 2 is rare and variably penetrant,” Human Molecular Genetics, vol. 5, no. 7, pp. 985–988, 1996.
[103]
P. St George-Hyslop, J. Haines, E. Rogaev et al., “Genetic evidence for a novel familial Alzheimer's disease locus on chromosome 14,” Nature Genetics, vol. 2, no. 4, pp. 330–334, 1992.
[104]
M. Tabaton and E. Tamagno, “The molecular link between β- and γ-secretase activity on the amyloid β precursor protein,” Cellular and Molecular Life Sciences, vol. 64, no. 17, pp. 2211–2218, 2007.
[105]
R. E. Tanzi, G. Vaula, D. M. Romano et al., “Assessment of amyloid β-protein precursor gene mutations in a large set of familial and sporadic Alzheimer disease cases,” American Journal of Human Genetics, vol. 51, no. 2, pp. 273–282, 1992.
[106]
C. Van Broeckhoven, H. Backhovens, M. Cruts et al., “Mapping of a gene predisposing to early-onset alzheimer's disease to chromosome 14q24.3,” Nature Genetics, vol. 2, no. 4, pp. 335–339, 1992.
[107]
R. Vassar, “BACE1: the β-secreiase enzyme in Alzheimer's disease,” Journal of Molecular Neuroscience, vol. 23, no. 1-2, pp. 105–113, 2004.
[108]
J. Kang and B. Muller-Hill, “Differential splicing of Alzheimer's disease amyloid A4 precursor RNA in rat tissues: PreA4695 mRNA is predominantly produced in rat and human brain,” Biochemical and Biophysical Research Communications, vol. 166, no. 3, pp. 1192–1200, 1990.
[109]
B. Anliker and U. Müller, “The functions of mammalian amyloid precursor protein and related amyloid precursor-like proteins,” Neurodegenerative Diseases, vol. 3, no. 4-5, pp. 239–246, 2006.
[110]
X. Cao and T. C. Südhof, “A transcriptivety active complex of APP with Fe65 and histone acetyltransferase Tip60,” Science, vol. 293, no. 5527, pp. 115–120, 2001.
[111]
H. Zheng and E. H. Koo, “The amyloid precursor protein: beyond amyloid,” Molecular Neurodegeneration, vol. 1, no. 1, article 5, 2006.
[112]
D. M. Walsh and D. J. Selkoe, “Aβ oligomers—a decade of discovery,” Journal of Neurochemistry, vol. 101, no. 5, pp. 1172–1184, 2007.
[113]
T. Iwatsubo, A. Odaka, N. Suzuki, H. Mizusawa, N. Nukina, and Y. Ihara, “Visualization of Aβ42(43) and Aβ40 in senile plaques with end-specific Aβ monoclonals: evidence that an initially deposited species is Aβ42(43),” Neuron, vol. 13, no. 1, pp. 45–53, 1994.
[114]
J. P. Cleary, D. M. Walsh, J. J. Hofmeister et al., “Natural oligomers of the amyloid-β protein specifically disrupt cognitive function,” Nature Neuroscience, vol. 8, no. 1, pp. 79–84, 2005.
[115]
K. N. Dahlgren, A. M. Manelli, W. Blaine Stine, L. K. Baker, G. A. Krafft, and M. J. Ladu, “Oligomeric and fibrillar species of amyloid-β peptides differentially affect neuronal viability,” The Journal of Biological Chemistry, vol. 277, no. 35, pp. 32046–32053, 2002.
[116]
C. A. McLean, R. A. Cherny, F. W. Fraser et al., “Soluble pool of Aβ amyloid as a determinant of severity of neurodegeneration in Alzheimer's disease,” Annals of Neurology, vol. 46, no. 6, pp. 860–866, 1999.
[117]
B. A. Chromy, R. J. Nowak, M. P. Lambert et al., “Self-assembly of Aβ1-42 into globular neurotoxins,” Biochemistry, vol. 42, no. 44, pp. 12749–12760, 2003.
[118]
W. L. Klein, W. B. Stine Jr., and D. B. Teplow, “Small assemblies of unmodified amyloid β-protein are the proximate neurotoxin in Alzheimer's disease,” Neurobiology of Aging, vol. 25, no. 5, pp. 569–580, 2004.
[119]
M. P. Lambert, A. K. Barlow, B. A. Chromy et al., “Diffusible, nonfibrillar ligands derived from Aβ1-42 are potent central nervous system neurotoxins,” Proceedings of the National Academy of Sciences of the United States of America, vol. 95, no. 11, pp. 6448–6453, 1998.
[120]
D. G. Georganopoulou, L. Chang, J. M. Nam et al., “Nanoparticle-based detection in cerebral spinal fluid of a soluble pathogenic biomarker for Alzheimer's disease,” Proceedings of the National Academy of Sciences of the United States of America, vol. 102, no. 7, pp. 2273–2276, 2005.
[121]
J. Hardy, “The amyloid hypothesis for Alzheimer's disease: a critical reappraisal,” Journal of Neurochemistry, vol. 110, no. 4, pp. 1129–1134, 2009.
[122]
T. Nakagawa, H. Zhu, N. Morishima et al., “Caspase-12 mediates endoplasmic-reticulum-specific apoptosis and cytotoxicity by amyloid-β,” Nature, vol. 403, no. 6765, pp. 98–103, 2000.
[123]
E. D. Roberson and L. Mucke, “100 Years and counting: prospects for defeating Alzheimer's disease,” Science, vol. 314, no. 5800, pp. 781–784, 2006.
[124]
C. Soto, “Unfolding the role of protein misfolding in neurodegenerative diseases,” Nature Reviews Neuroscience, vol. 4, no. 1, pp. 49–60, 2003.
[125]
M. Hong and V. M. Y. Lee, “Insulin and insulin-like growth factor-1 regulate tau phosphorylation in cultured human neurons,” The Journal of Biological Chemistry, vol. 272, no. 31, pp. 19547–19553, 1997.
[126]
M. Schubert, D. P. Brazil, D. J. Burks et al., “Insulin receptor substrate-2 deficiency impairs brain growth and promotes tau phosphorylation,” Journal of Neuroscience, vol. 23, no. 18, pp. 7084–7092, 2003.
[127]
H. Dudek, S. R. Datta, T. F. Franke et al., “Regulation of neuronal survival by the serine-threonine protein kinase Akt,” Science, vol. 275, no. 5300, pp. 661–665, 1997.
[128]
Y. H. Ling, L. Liebes, B. Ng et al., “PS-341, a novel proteasome inhibitor, induces Bcl-2 phosphorylation and cleavage in association with G2-M phase arrest and apoptosis,” Molecular Cancer Therapeutics, vol. 1, no. 10, pp. 841–849, 2002.
[129]
L. Xie, E. Helmerhorst, K. Taddei, B. Plewright, W. Van Bronswijk, and R. Martins, “Alzheimer's beta-amyloid peptides compete for insulin binding to the insulin receptor,” The Journal of Neuroscience, vol. 22, no. 10, Article ID RC221, 2002.
[130]
C. M. Cheng, V. Tseng, J. Wang, D. Wang, L. Matyakhina, and C. A. Bondy, “Tau is hyperphosphorylated in the insulin-like growth factor-I null brain,” Endocrinology, vol. 146, no. 12, pp. 5086–5091, 2005.
[131]
M. Schubert, D. Gautam, D. Surjo et al., “Role for neuronal insulin resistance in neurodegenerative diseases,” Proceedings of the National Academy of Sciences of the United States of America, vol. 101, no. 9, pp. 3100–3105, 2004.
[132]
B. De Strooper, “Aph-1, Pen-2, and Nicastrin with Presenilin generate an active γ-Secretase complex,” Neuron, vol. 38, no. 1, pp. 9–12, 2003.
[133]
R. M.D. Holsinger, C. A. McLean, K. Beyreuther, C. L. Masters, and G. Evin, “Increased expression of the amyloid precursor β-secretase in Alzheimer's disease,” Annals of Neurology, vol. 51, no. 6, pp. 783–786, 2002.
[134]
S. Iwasaki, D. Harada, S. I. Usami, M. Nagura, T. Takeshita, and T. Hoshino, “Association of clinical features with mutation of TECTA in a family with autosomal dominant hearing loss,” Archives of Otolaryngology, vol. 128, no. 8, pp. 913–917, 2002.
[135]
S. Sinha, J. P. Anderson, R. Barbour et al., “Purification and cloning of amyloid precursor protein β-secretase from human brain,” Nature, vol. 402, no. 6761, pp. 537–540, 1999.
[136]
S. Freude, M. M. Hettich, C. Schumann et al., “Neuronal IGF-1 resistance reduces Aβ accumulation and protects against premature death in a model of Alzheimer's disease,” The FASEB Journal, vol. 23, no. 10, pp. 3315–3324, 2009.
[137]
O. St？hr, K. Schilbach, L. Moll et al., “Insulin receptor signaling mediates APP processing and β-amyloid accumulation without altering survival in a transgenic mouse model of Alzheimer's disease,” Age. In press.
[138]
J. L. Jankowsky, H. H. Slunt, T. Ratovitski, N. A. Jenkins, N. G. Copeland, and D. R. Borchelt, “Co-expression of multiple transgenes in mouse CNS: a comparison of strategies,” Biomolecular Engineering, vol. 17, no. 6, pp. 157–165, 2001.
[139]
E. Cohen, J. F. Paulsson, P. Blinder et al., “Reduced IGF-1 signaling delays age-associated proteotoxicity in mice,” Cell, vol. 139, no. 6, pp. 1157–1169, 2009.
[140]
E. Cohen, J. Bieschke, R. M. Perciavalle, J. W. Kelly, and A. Dillin, “Opposing activities protect against age-onset proteotoxicity,” Science, vol. 313, no. 5793, pp. 1604–1610, 2006.
[141]
K. U. Birkenkamp and P. J. Coffer, “Regulation of cell survival and proliferation by the FOXO (Forkhead box, class O) subfamily of Forkhead transcription factors,” Biochemical Society Transactions, vol. 31, no. 1, pp. 292–297, 2003.
[142]
A. L. Hsu, C. T. Murphy, and C. Kenyon, “Regulation of aging and age-related disease by DAF-16 and heat-shock factor,” Science, vol. 300, no. 5622, pp. 1142–1145, 2003.
[143]
W. Qin, W. Zhao, L. Ho et al., “Regulation of forkhead transcription factor FoxO3a contributes to calorie restriction-induced prevention of Alzheimer's disease-type amyloid neuropathology and spatial memory deterioration,” Annals of the New York Academy of Sciences, vol. 1147, pp. 335–347, 2008.
[144]
R. E. Tanzi, R. D. Moir, and S. L. Wagner, “Clearance of Alzheimer's Aβ peptide: the many roads to perdition,” Neuron, vol. 43, no. 5, pp. 605–608, 2004.
[145]
E. Carro, J. L. Trejo, T. Gomez-Isla, D. LeRoith, and I. Torres-Aleman, “Serum insulin-like growth factor I regulates brain amyloid-β levels,” Nature Medicine, vol. 8, no. 12, pp. 1390–1397, 2002.
[146]
A. Astrinidis and E. P. Henske, “Tuberous sclerosis complex: linking growth and energy signaling pathways with human disease,” Oncogene, vol. 24, no. 50, pp. 7475–7481, 2005.
[147]
N. Hay and N. Sonenberg, “Upstream and downstream of mTOR,” Genes and Development, vol. 18, no. 16, pp. 1926–1945, 2004.
[148]
H. Nojima, C. Tokunaga, S. Eguchi et al., “The mammalian target of rapamycin (mTOR) partner, raptor, binds the mTOR substrates p70 S6 kinase and 4E-BP1 through their TOR signaling (TOS) motif,” The Journal of Biological Chemistry, vol. 278, no. 18, pp. 15461–15464, 2003.
[149]
N. Oshiro, K. I. Yoshino, S. Hidayat et al., “Dissociation of raptor from mTOR is a mechanism of rapamycin-induced inhibition of mTOR function,” Genes to Cells, vol. 9, no. 4, pp. 359–366, 2004.
[150]
D. E. Harrison, R. Strong, Z. D. Sharp et al., “Rapamycin fed late in life extends lifespan in genetically heterogeneous mice,” Nature, vol. 460, no. 7253, pp. 392–395, 2009.
[151]
S. Majumder, A. Caccamo, D. X. Medina et al., “Lifelong rapamycin administration ameliorates age-dependent cognitive deficits by reducing IL-1β and enhancing NMDA signaling,” Aging Cell, vol. 11, no. 2, pp. 326–335, 2012.
