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BioMed Research International
Volume 2016, Article ID 2589276, 17 pages
http://dx.doi.org/10.1155/2016/2589276
Review Article

Therapies for Prevention and Treatment of Alzheimer’s Disease

Laboratorio de Investigación Genética, Facultad de Química, Universidad Autónoma de Querétaro, Cerro de las Campanas S/N, Centro Universitario, 76010 Santiago de Querétaro, QRO, Mexico

Received 23 March 2016; Revised 31 May 2016; Accepted 5 June 2016

Academic Editor: Yiying Zhang

Copyright © 2016 J. Mendiola-Precoma et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Linked References

  1. C. Van Cauwenberghe, C. Van Broeckhoven, and K. Sleegers, “The genetic landscape of Alzheimer disease: clinical implications and perspectives,” Genetics in Medicine, vol. 18, no. 5, pp. 421–430, 2015. View at Publisher · View at Google Scholar
  2. S. Chakrabarti, V. K. Khemka, A. Banerjee, G. Chatterjee, A. Ganguly, and A. Biswas, “Metabolic risk factors of sporadic Alzheimer’s disease: implications in the pathology, pathogenesis and treatment,” Aging and Disease, vol. 6, no. 4, pp. 282–299, 2015. View at Publisher · View at Google Scholar · View at Scopus
  3. T. D. Bird, “Early-onset familial Alzheimer disease,” in GeneReviews, R. Pagon, M. Adam, H. Ardinger et al., Eds., pp. 1–42, University of Washington, Seattle, Seattle, Wash, USA, 2012. View at Google Scholar
  4. L. W. Chu, “Alzheimer’s disease: early diagnosis and treatment,” Hong Kong Medical Journal, vol. 18, no. 3, pp. 228–237, 2012. View at Google Scholar · View at Scopus
  5. X. Sun, W. Chen, and Y. Wang, “β-Amyloid: the key peptide in the pathogenesis of Alzheimer’s disease,” Frontiers in Pharmacology, vol. 6, pp. 1–9, 2015. View at Publisher · View at Google Scholar
  6. C. Cervellati, P. L. Wood, A. Romani et al., “Oxidative challenge in Alzheimer’s disease: state of knowledge and future needs,” Journal of Investigative Medicine, vol. 64, no. 1, pp. 21–32, 2016. View at Publisher · View at Google Scholar
  7. B. De Strooper and E. Karran, “The cellular phase of Alzheimer’s disease,” Cell, vol. 164, no. 4, pp. 603–615, 2016. View at Publisher · View at Google Scholar · View at Scopus
  8. C. Spuch, S. Ortolano, and C. Navarro, “LRP-1 and LRP-2 receptors function in the membrane neuron. Trafficking mechanisms and proteolytic processing in Alzheimer’s disease,” Frontiers in Physiology, vol. 3, article 269, pp. 1–14, 2012. View at Publisher · View at Google Scholar · View at Scopus
  9. S. H. Barage and K. D. Sonawane, “Amyloid cascade hypothesis: pathogenesis and therapeutic strategies in Alzheimer’s disease,” Neuropeptides, vol. 52, pp. 1–18, 2015. View at Publisher · View at Google Scholar · View at Scopus
  10. G. Šimić, M. B. Leko, S. Wray et al., “Tau protein hyperphosphorylation and aggregation in alzheimer’s disease and other tauopathies, and possible neuroprotective strategies,” Biomolecules, vol. 6, no. 6, pp. 1–28, 2016. View at Google Scholar
  11. A. Contestabile, “The history of the cholinergic hypothesis,” Behavioural Brain Research, vol. 221, no. 2, pp. 334–340, 2011. View at Publisher · View at Google Scholar · View at Scopus
  12. J. Folch, I. Patraca, N. Martínez et al., “The role of leptin in the sporadic form of Alzheimer’s disease. Interactions with the adipokines amylin, ghrelin and the pituitary hormone prolactin,” Life Sciences, vol. 140, pp. 19–28, 2015. View at Publisher · View at Google Scholar · View at Scopus
  13. L. Y. Di Marco, A. Venneri, E. Farkas, P. C. Evans, A. Marzo, and A. F. Frangi, “Vascular dysfunction in the pathogenesis of Alzheimer’s disease—a review of endothelium-mediated mechanisms and ensuing vicious circles,” Neurobiology of Disease, vol. 82, pp. 593–606, 2015. View at Publisher · View at Google Scholar · View at Scopus
  14. P. Gamba, G. Testa, S. Gargiulo, E. Staurenghi, G. Poli, and G. Leonarduzzi, “Oxidized cholesterol as the driving force behind the development of Alzheimer’s disease,” Frontiers in Aging Neuroscience, vol. 7, article 119, 2015. View at Publisher · View at Google Scholar · View at Scopus
  15. L. Xu, X. Wu, R. Li et al., “Prediction of progressive mild cognitive impairment by multi-modal neuroimaging biomarkers,” Journal of Alzheimer’s Disease, vol. 51, no. 4, pp. 1045–1056, 2016. View at Publisher · View at Google Scholar
  16. S. Ramírez-Díaz, G. Albert-Meza, J. Ávila-Fuentes et al., Enfermedad de Alzheimer: Presente y Futuro, Planeación y Desarrollo, Monterrey, Mexico, 2011.
  17. A. Christensen and C. J. Pike, “Menopause, obesity and inflammation: interactive risk factors for Alzheimer’s disease,” Frontiers in Aging Neuroscience, vol. 7, article 130, pp. 1–14, 2015. View at Publisher · View at Google Scholar
  18. Z. Chen and C. Zhong, “Oxidative stress in Alzheimer’s disease,” Neuroscience Bulletin, vol. 30, no. 2, pp. 271–281, 2014. View at Publisher · View at Google Scholar · View at Scopus
  19. L. B. Haim, M.-A. Carrillo-de Sauvage, K. Ceyzériat, and C. Escartin, “Elusive roles for reactive astrocytes in neurodegenerative diseases,” Frontiers in Cellular Neuroscience, vol. 9, article 278, pp. 1–27, 2015. View at Publisher · View at Google Scholar · View at Scopus
  20. Y. Huang and R. W. Mahley, “Neurobiology of Disease Apolipoprotein E: structure and function in lipid metabolism, neurobiology, and Alzheimer’s diseases,” Neurobiology of Disease, vol. 72, pp. 3–12, 2014. View at Publisher · View at Google Scholar
  21. V. Van-Giau, E. Bagyinszky, S. S.-A. An, and S. Y. Kim, “Role of apolipoprotein E in neurodegenerative diseases,” Neuropsychiatric Disease and Treatment, vol. 11, pp. 1723–1737, 2015. View at Publisher · View at Google Scholar · View at Scopus
  22. I. H. K. Dias, M. C. Polidori, and H. R. Griffiths, “Hypercholesterolaemia-induced oxidative stress at the blood-brain barrier,” Biochemical Society Transactions, vol. 42, no. 4, pp. 1001–1005, 2014. View at Publisher · View at Google Scholar · View at Scopus
  23. Z. Xue-Shan, W. Qi, R. Zhong et al., “Imbalanced cholesterol metabolism in Alzheimer’s disease,” Clinica Chimica Acta, vol. 456, pp. 107–114, 2016. View at Publisher · View at Google Scholar
  24. G. Verdile, K. N. Keane, V. F. Cruzat et al., “Inflammation and oxidative stress: the molecular connectivity between insulin resistance, obesity, and Alzheimer’s disease,” Mediators of Inflammation, vol. 2015, Article ID 105828, 17 pages, 2015. View at Publisher · View at Google Scholar · View at Scopus
  25. J. M. Walker and F. E. Harrison, “Shared neuropathological characteristics of obesity, type 2 diabetes and Alzheimer’s disease: impacts on cognitive decline,” Nutrients, vol. 7, no. 9, pp. 7332–7357, 2015. View at Publisher · View at Google Scholar · View at Scopus
  26. R. F. de Bruijn and M. A. Ikram, “Cardiovascular risk factors and future risk of Alzheimer’s disease,” BMC Medicine, vol. 12, no. 1, article 130, pp. 1–9, 2014. View at Publisher · View at Google Scholar · View at Scopus
  27. D. A. Butterfield, F. Di Domenico, and E. Barone, “Elevated risk of type 2 diabetes for development of Alzheimer disease: a key role for oxidative stress in brain,” Biochimica et Biophysica Acta—Molecular Basis of Disease, vol. 1842, no. 9, pp. 1693–1706, 2014. View at Publisher · View at Google Scholar · View at Scopus
  28. R. Sandhir and S. Gupta, “Molecular and biochemical trajectories from diabetes to Alzheimer’s disease?: a critical appraisal,” World Journal of Diabetes, vol. 6, no. 12, pp. 1223–1242, 2015. View at Google Scholar
  29. P. G. Ridge, M. T. Ebbert, and J. S. Kauwe, “Genetics of Alzheimer’s disease,” BioMed Research International, vol. 2013, Article ID 254954, 13 pages, 2013. View at Publisher · View at Google Scholar
  30. D. M. Holtzman, J. Herz, and G. Bu, “Apolipoprotein E and apolipoprotein E receptors: normal biology and roles in Alzheimer disease,” Cold Spring Harbor Perspectives in Medicine, vol. 2, no. 3, Article ID a006312, 2012. View at Publisher · View at Google Scholar
  31. C.-C. Liu, T. Kanekiyo, H. Xu, and G. Bu, “Apolipoprotein e and Alzheimer disease: risk, mechanisms and therapy,” Nature Reviews Neurology, vol. 9, no. 2, pp. 106–118, 2013. View at Publisher · View at Google Scholar · View at Scopus
  32. A. M. Manelli, W. B. Stine, L. J. Van Eldik, and M. J. LaDu, “ApoE and Abeta1-42 interactions: effects of isoform and conformation on structure and function,” Journal of Molecular Neuroscience, vol. 23, no. 3, pp. 235–246, 2004. View at Publisher · View at Google Scholar · View at Scopus
  33. E. H. Corder, A. M. Saunders, W. J. Strittmatter et al., “Gene dose of apolipoprotein e type 4 allele and the risk of Alzheimer’s disease in late onset families,” Science, vol. 261, no. 5123, pp. 921–923, 1993. View at Publisher · View at Google Scholar
  34. Y. Gu, Q. R. Razlighi, L. B. Zahodne et al., “Brain amyloid deposition and longitudinal cognitive decline in nondemented older subjects: results from a multi- ethnic population,” PLoS ONE, vol. 116, pp. 1–14, 2015. View at Google Scholar
  35. J. B. S. Langbaum, K. Chen, R. J. Caselli et al., “Hypometabolism in Alzheimer-affected brain regions in cognitively healthy latino individuals carrying the apolipoprotein E ε4 allele,” Archives of Neurology, vol. 67, no. 4, pp. 462–468, 2010. View at Publisher · View at Google Scholar · View at Scopus
  36. L. Xie, H. Yan, L. Shi et al., “Association between CYP17A1 rs3824755 and rs743572 gene polymorphisms and Alzheimer’s disease in the Chinese Han population,” Neuroscience Letters, vol. 618, pp. 77–82, 2016. View at Publisher · View at Google Scholar
  37. M.-X. Tang, G. Maestre, W.-Y. Tsai et al., “Relative risk of Alzheimer disease and age-at-onset distributions, based on APOE genotypes among elderly African Americans, Caucasians, and Hispanics in New York City,” The American Journal of Human Genetics, vol. 58, no. 3, pp. 574–584, 1996. View at Google Scholar · View at Scopus
  38. R. M. Corbo and R. Scacchp, “Apolipoprotein E (APOE) allele distribution in the world. Is APOE4 a ‘thrifty’ allele?” Annals of Human Genetics, vol. 63, no. 4, pp. 301–310, 1999. View at Publisher · View at Google Scholar · View at Scopus
  39. Y. L. Chai, H. K.-H. Yeo, J. Wang et al., “Apolipoprotein ɛ4 is associated with dementia and cognitive impairment predominantly due to Alzheimer’s disease and not with vascular cognitive impairment: a Singapore-based cohort,” Journal of Alzheimer’s Disease, vol. 51, no. 4, pp. 1111–1118, 2016. View at Publisher · View at Google Scholar
  40. R. Wang, L. Fratiglioni, E. J. Laukka et al., “Effects of vascular risk factors and APOE ε4 on white matter integrity and cognitive decline,” Neurology, vol. 84, no. 11, pp. 1128–1135, 2015. View at Publisher · View at Google Scholar · View at Scopus
  41. C. M. Karch and A. M. Goate, “Alzheimer’s disease risk genes and mechanisms of disease pathogenesis,” Biological Psychiatry, vol. 77, no. 1, pp. 43–51, 2015. View at Publisher · View at Google Scholar · View at Scopus
  42. J. R. P. Prasanthi, M. Schrag, B. Dasari et al., “Deferiprone reduces amyloid-β and tau phosphorylation levels but not reactive oxygen species generation in hippocampus of rabbits fed a cholesterol-enriched diet,” Journal of Alzheimer’s Disease, vol. 30, no. 1, pp. 167–182, 2012. View at Publisher · View at Google Scholar · View at Scopus
  43. S. Kosari, E. Badoer, J. C. D. Nguyen, A. S. Killcross, and T. A. Jenkins, “Effect of western and high fat diets on memory and cholinergic measures in the rat,” Behavioural Brain Research, vol. 235, no. 1, pp. 98–103, 2012. View at Publisher · View at Google Scholar · View at Scopus
  44. W. L. F. Lim, I. J. Martins, and R. N. Martins, “The involvement of lipids in alzheimer’s disease,” Journal of Genetics and Genomics, vol. 41, no. 5, pp. 261–274, 2014. View at Publisher · View at Google Scholar · View at Scopus
  45. L. Puglielli, B. C. Ellis, A. J. Saunders, and D. M. Kovacs, “Ceramide stabilizes β-site amyloid precursor protein-cleaving enzyme 1 and promotes amyloid β-peptide biogenesis,” The Journal of Biological Chemistry, vol. 278, no. 22, pp. 19777–19783, 2003. View at Publisher · View at Google Scholar · View at Scopus
  46. C. Marquer, V. Devauges, J.-C. Cossec et al., “Local cholesterol increase triggers amyloid precursor protein-Bace1 clustering in lipid rafts and rapid endocytosis,” The FASEB Journal, vol. 25, no. 4, pp. 1295–1305, 2011. View at Publisher · View at Google Scholar · View at Scopus
  47. L. K. Cuddy, W. Winick-Ng, and R. J. Rylett, “Regulation of the high-affinity choline transporter activity and trafficking by its association with cholesterol-rich lipid rafts,” Journal of Neurochemistry, vol. 128, no. 5, pp. 725–740, 2014. View at Publisher · View at Google Scholar · View at Scopus
  48. V. A. M. Villar, S. Cuevas, X. Zheng, and P. A. Jose, “Localization and signaling of GPCRs in lipid rafts,” Methods in Cell Biology, vol. 132, pp. 3–23, 2016. View at Publisher · View at Google Scholar · View at Scopus
  49. C. Ullrich, M. Pirchl, and C. Humpel, “Hypercholesterolemia in rats impairs the cholinergic system and leads to memory deficits,” Molecular and Cellular Neuroscience, vol. 45, no. 4, pp. 408–417, 2010. View at Publisher · View at Google Scholar · View at Scopus
  50. Y. Kim, C. Kim, H. Y. Jang, I. Mook-Jung, and B. Kim, “Inhibition of cholesterol biosynthesis reduces γ-secretase activity and amyloid-β generation,” Journal of Alzheimer’s Disease, vol. 51, no. 4, pp. 1057–1068, 2016. View at Publisher · View at Google Scholar
  51. E. Kojro, G. Gimpl, S. Lammich, W. März, and F. Fahrenholz, “Low cholesterol stimulates the nonamyloidogenic pathway by its effect on the α-secretase ADAM 10,” Proceedings of the National Academy of Sciences of the United States of America, vol. 98, no. 10, pp. 5815–5820, 2001. View at Publisher · View at Google Scholar · View at Scopus
  52. V. Vingtdeux and P. Marambaud, “Identification and biology of α-secretase,” Journal of Neurochemistry, vol. 120, no. 1, pp. 34–45, 2012. View at Publisher · View at Google Scholar · View at Scopus
  53. J. Popp, S. Meichsner, H. Kölsch et al., “Cerebral and extracerebral cholesterol metabolism and CSF markers of Alzheimer’s disease,” Biochemical Pharmacology, vol. 86, no. 1, pp. 37–42, 2013. View at Publisher · View at Google Scholar · View at Scopus
  54. J. Poirier, J. Miron, C. Picard et al., “Apolipoprotein E and lipid homeostasis in the etiology and treatment of sporadic Alzheimer’s disease,” Neurobiology of Aging, vol. 35, no. 2, pp. S3–S10, 2014. View at Publisher · View at Google Scholar · View at Scopus
  55. G. Marwarha and O. Ghribi, “Does the oxysterol 27-hydroxycholesterol underlie Alzheimer’s disease—Parkinson’s disease overlap?” Experimental Gerontology, vol. 68, pp. 13–18, 2015. View at Publisher · View at Google Scholar · View at Scopus
  56. V. Leoni and C. Caccia, “Oxysterols as biomarkers in neurodegenerative diseases,” Chemistry and Physics of Lipids, vol. 164, no. 6, pp. 515–524, 2011. View at Publisher · View at Google Scholar · View at Scopus
  57. M. Sharma, M. Tiwari, and R. K. Tiwari, “Hyperhomocysteinemia: impact on neurodegenerative diseases,” Basic and Clinical Pharmacology and Toxicology, vol. 117, no. 5, pp. 287–296, 2015. View at Publisher · View at Google Scholar · View at Scopus
  58. B. A. Maron and J. Loscalzo, “The treatment of hyperhomocysteinemia,” Annual Review of Medicine, vol. 60, pp. 39–54, 2009. View at Publisher · View at Google Scholar · View at Scopus
  59. R. Poddar and S. Paul, “Homocysteine-NMDA receptor-mediated activation of extracellular signal-regulated kinase leads to neuronal cell death,” Journal of Neurochemistry, vol. 110, no. 3, pp. 1095–1106, 2009. View at Publisher · View at Google Scholar · View at Scopus
  60. S. Li, M. Jin, T. Koeglsperger, N. E. Shepardson, G. M. Shankar, and D. J. Selkoe, “Soluble a β oligomers inhibit long-term potentiation through a mechanism involving excessive activation of extrasynaptic NR2B-containing NMDA receptors,” Journal of Neuroscience, vol. 31, no. 18, pp. 6627–6638, 2011. View at Publisher · View at Google Scholar · View at Scopus
  61. J. H. Birnbaum, J. Bali, L. Rajendran, R. M. Nitsch, and C. Tackenberg, “Calcium flux-independent NMDA receptor activity is required for Aβ oligomer-induced synaptic loss,” Cell Death & Disease, vol. 6, no. 6, Article ID e1791, 2015. View at Publisher · View at Google Scholar
  62. M. Wiesmann, C. Capone, V. Zerbi et al., “Hypertension impairs cerebral blood flow in a mouse model for Alzheimer’s disease,” Current Alzheimer Research, vol. 12, no. 10, pp. 914–922, 2015. View at Publisher · View at Google Scholar
  63. E. Joas, K. Bäckman, D. Gustafson et al., “Blood pressure trajectories from midlife to late life in relation to dementia in women followed for 37 years,” Hypertension, vol. 59, no. 4, pp. 796–801, 2012. View at Publisher · View at Google Scholar · View at Scopus
  64. C. N. H. Abheiden, R. Van Doornik, A. M. Aukes, W. M. Van Der Flier, P. Scheltens, and C. J. M. De Groot, “Hypertensive disorders of pregnancy appear not to be associated with Alzheimer’s disease later in life,” Dementia and Geriatric Cognitive Disorders Extra, vol. 5, no. 3, pp. 375–385, 2015. View at Publisher · View at Google Scholar
  65. Y. Lu, F. R. Day, S. Gustafsson et al., “New loci for body fat percentage reveal link between adiposity and cardiometabolic disease risk,” Nature Communications, vol. 7, Article ID 10495, 2016. View at Publisher · View at Google Scholar
  66. E. Pedditizi, R. Peters, and N. Beckett, “The risk of overweight/obesity in mid-life and late life for the development of dementia: a systematic review and meta-analysis of longitudinal studies,” Age and Ageing, vol. 45, no. 1, pp. 14–21, 2016. View at Publisher · View at Google Scholar
  67. J. P. Thaler, C.-X. Yi, E. A. Schur et al., “Obesity is associated with hypothalamic injury in rodents and humans,” The Journal of Clinical Investigation, vol. 122, no. 1, pp. 153–162, 2012. View at Publisher · View at Google Scholar · View at Scopus
  68. D. J. Bonda, J. G. Stone, S. L. Torres et al., “Dysregulation of leptin signaling in Alzheimer disease: evidence for neuronal leptin resistance,” Journal of Neurochemistry, vol. 128, no. 1, pp. 162–172, 2014. View at Publisher · View at Google Scholar · View at Scopus
  69. A. Jayaraman, D. Lent-Schochet, and C. J. Pike, “Diet-induced obesity and low testosterone increase neuroinflammation and impair neural function,” Journal of Neuroinflammation, vol. 11, article 162, 2014. View at Publisher · View at Google Scholar · View at Scopus
  70. V. A. Moser and C. J. Pike, “Obesity and sex interact in the regulation of Alzheimer’s disease,” Neuroscience & Biobehavioral Reviews, 2015. View at Publisher · View at Google Scholar
  71. N. D. Barnard, A. E. Bunner, and U. Agarwal, “Saturated and trans fats and dementia: a systematic review,” Neurobiology of Aging, vol. 35, supplement 2, pp. S65–S73, 2014. View at Publisher · View at Google Scholar · View at Scopus
  72. M. C. Morris and C. C. Tangney, “Dietary fat composition and dementia risk,” Neurobiology of Aging, vol. 35, supplement 2, pp. S59–S64, 2014. View at Publisher · View at Google Scholar · View at Scopus
  73. M. Maesako, M. Uemura, Y. Tashiro et al., “High fat diet enhances β-site cleavage of amyloid precursor protein (APP) via promoting β-site APP cleaving enzyme 1/adaptor protein 2/clathrin complex formation,” PLoS ONE, vol. 10, no. 9, Article ID e0131199, pp. 1–16, 2015. View at Publisher · View at Google Scholar · View at Scopus
  74. E. M. Knight, I. V. A. Martins, S. Gümüsgöz, S. M. Allan, and C. B. Lawrence, “Neurobiology of Aging High-fat diet-induced memory impairment in triple-transgenic Alzheimer’s disease (3xTgAD) mice is independent of changes in amyloid and tau pathology,” Neurobiology of Aging, vol. 35, no. 8, pp. 1821–1832, 2014. View at Publisher · View at Google Scholar
  75. D. Petrov, I. Pedrós, G. Artiach et al., “High-fat diet-induced deregulation of hippocampal insulin signaling and mitochondrial homeostasis deficiences contribute to Alzheimer disease pathology in rodents,” Biochimica et Biophysica Acta—Molecular Basis of Disease, vol. 1852, no. 9, pp. 1687–1699, 2015. View at Publisher · View at Google Scholar · View at Scopus
  76. A. L. Fitzpatrick, L. H. Kuller, O. L. Lopez et al., “Midlife and late-life obesity and the risk of dementia: cardiovascular health study,” Archives of Neurology, vol. 66, no. 3, pp. 336–342, 2009. View at Publisher · View at Google Scholar · View at Scopus
  77. C. A. Magalhães, M. G. Carvalho, L. P. Sousa, P. Caramelli, and K. B. Gomes, “Leptin in Alzheimer’s disease,” Clinica Chimica Acta, vol. 450, pp. 162–168, 2015. View at Publisher · View at Google Scholar · View at Scopus
  78. N. Qizilbash, J. Gregson, M. E. Johnson et al., “BMI and risk of dementia in two million people over two decades: a retrospective cohort study,” The Lancet Diabetes and Endocrinology, vol. 3, no. 6, pp. 431–436, 2015. View at Publisher · View at Google Scholar · View at Scopus
  79. L. Letra, I. Santana, and R. Seiça, “Obesity as a risk factor for Alzheimer’s disease: the role of adipocytokines,” Metabolic Brain Disease, vol. 29, no. 3, pp. 563–568, 2014. View at Publisher · View at Google Scholar · View at Scopus
  80. T. L. Platt, T. L. Beckett, K. Kohler, D. M. Niedowicz, and M. P. Murphy, “Obesity, diabetes, and leptin resistance promote tau pathology in a mouse model of disease,” Neuroscience, vol. 315, pp. 162–174, 2016. View at Publisher · View at Google Scholar · View at Scopus
  81. I. A. C. Arnoldussen, A. J. Kiliaan, and D. R. Gustafson, “Obesity and dementia: adipokines interact with the brain,” European Neuropsychopharmacology, vol. 24, no. 12, pp. 1982–1999, 2014. View at Publisher · View at Google Scholar · View at Scopus
  82. A. Aguilar-Valles, W. Inoue, C. Rummel, and G. N. Luheshi, “Obesity, adipokines and neuroinflammation,” Neuropharmacology, vol. 96, pp. 124–134, 2015. View at Publisher · View at Google Scholar · View at Scopus
  83. M. Ishii and C. Iadecola, “Adipocyte-derived factors in age-related dementia and their contribution to vascular and Alzheimer pathology,” Biochimica et Biophysica Acta (BBA): Molecular Basis of Disease, vol. 1862, no. 5, pp. 966–974, 2016. View at Publisher · View at Google Scholar
  84. H. Münzberg, “Leptin-signaling pathways and leptin resistance,” Forum of Nutrition, vol. 63, pp. 123–132, 2010. View at Publisher · View at Google Scholar · View at Scopus
  85. J. Ma, W. Zhang, H. Wang et al., “Peripheral blood adipokines and insulin levels in patients with Alzheimer’s disease: a replication study and meta-analysis,” Current Alzheimer Research, vol. 13, no. 3, pp. 223–233, 2016. View at Publisher · View at Google Scholar
  86. P. Rajagopalan, A. W. Toga, C. R. Jack, M. W. Weiner, and P. M. Thompson, “Fat-mass-related hormone, plasma leptin, predicts brain volumes in the elderly,” NeuroReport, vol. 24, no. 2, pp. 58–62, 2013. View at Publisher · View at Google Scholar · View at Scopus
  87. A. Zeki Al Hazzouri, K. L. Stone, M. N. Haan, and K. Yaffe, “Leptin, mild cognitive impairment, and dementia among elderly women,” Journals of Gerontology, Series A: Biological Sciences and Medical Sciences, vol. 68, no. 2, pp. 175–180, 2013. View at Publisher · View at Google Scholar · View at Scopus
  88. H. Münzberg and M. G. Myers Jr., “Molecular and anatomical determinants of central leptin resistance,” Nature Neuroscience, vol. 8, no. 5, pp. 566–570, 2005. View at Publisher · View at Google Scholar · View at Scopus
  89. S. J. Greco, A. Hamzelou, J. M. Johnston, M. A. Smith, J. W. Ashford, and N. Tezapsidis, “Leptin boosts cellular metabolism by activating AMPK and the sirtuins to reduce tau phosphorylation and β-amyloid in neurons,” Biochemical and Biophysical Research Communications, vol. 414, no. 1, pp. 170–174, 2011. View at Publisher · View at Google Scholar · View at Scopus
  90. G. H. Doherty, “Obesity and the ageing brain: could leptin play a role in neurodegeneration?” Current Gerontology and Geriatrics Research, vol. 2011, Article ID 708154, 8 pages, 2011. View at Publisher · View at Google Scholar · View at Scopus
  91. G. Marwarha, S. Raza, C. Meiers, and O. Ghribi, “Leptin attenuates BACE1 expression and amyloid-β genesis via the activation of SIRT1 signaling pathway,” Biochimica et Biophysica Acta (BBA)—Molecular Basis of Disease, vol. 1842, no. 9, pp. 1587–1595, 2014. View at Publisher · View at Google Scholar · View at Scopus
  92. G. V. Ronnett, S. Ramamurthy, A. M. Kleman, L. E. Landree, and S. Aja, “AMPK in the brain: its roles in energy balance and neuroprotection,” Journal of Neurochemistry, vol. 109, no. 1, pp. 17–23, 2009. View at Publisher · View at Google Scholar · View at Scopus
  93. M. Dhar, G. A. Wayman, M. Zhu, T. J. Lambert, M. A. Davare, and S. M. Appleyard, “Leptin-induced spine formation requires TrpC channels and the CaM kinase cascade in the hippocampus,” The Journal of Neuroscience, vol. 34, no. 30, pp. 10022–10033, 2014. View at Publisher · View at Google Scholar
  94. Y. Takemura, K. Walsh, and N. Ouchi, “Adiponectin and cardiovascular inflammatory responses,” Current Atherosclerosis Reports, vol. 9, no. 3, pp. 238–243, 2007. View at Publisher · View at Google Scholar · View at Scopus
  95. M. Blüher and C. S. Mantzoros, “From leptin to other adipokines in health and disease: facts and expectations at the beginning of the 21st century,” Metabolism: Clinical and Experimental, vol. 64, no. 1, pp. 131–145, 2015. View at Publisher · View at Google Scholar · View at Scopus
  96. C. K. Chakraborti, “Role of adiponectin and some other factors linking type 2 diabetes mellitus and obesity,” World Journal of Diabetes, vol. 6, no. 15, pp. 1296–1308, 2015. View at Publisher · View at Google Scholar
  97. K.-H. Chan, K. S.-L. Lam, O.-Y. Cheng et al., “Adiponectin is protective against oxidative stress induced cytotoxicity in amyloid-beta neurotoxicity,” PLoS ONE, vol. 7, no. 12, Article ID e52354, 2012. View at Publisher · View at Google Scholar · View at Scopus
  98. N. García-Casares, J. A. García-Arnés, J. Rioja et al., “Alzheimer’s like brain changes correlate with low adiponectin plasma levels in type 2 diabetic patients,” Journal of Diabetes and Its Complications, vol. 30, no. 2, pp. 281–286, 2016. View at Publisher · View at Google Scholar · View at Scopus
  99. L. Dukic, A.-M. Simundic, I. Martinic-Popovic et al., “The role of human kallikrein 6, clusterin and adiponectin as potential blood biomarkers of dementia,” Clinical Biochemistry, vol. 49, no. 3, pp. 213–218, 2016. View at Publisher · View at Google Scholar · View at Scopus
  100. G. Marwarha, S. Raza, J. R. P. Prasanthi, and O. Ghribi, “Gadd153 and NF-κB crosstalk regulates 27-hydroxycholesterol-induced increase in BACE1 and β-amyloid production in human neuroblastoma SH-SY5Y cells,” PLoS ONE, vol. 8, no. 8, Article ID e70773, 2013. View at Publisher · View at Google Scholar · View at Scopus
  101. L. Bernardino, F. Agasse, B. Silva, R. Ferreira, S. Grade, and J. O. Malva, “Tumor necrosis factor-α modulates survival, proliferation, and neuronal differentiation in neonatal subventricular zone cell cultures,” Stem Cells, vol. 26, no. 9, pp. 2361–2371, 2008. View at Publisher · View at Google Scholar · View at Scopus
  102. S. Li, J. Deng, H. Hou et al., “Specific antibody binding to the APP672699 region shifts APP processing from α- To β-cleavage,” Cell Death and Disease, vol. 5, no. 8, Article ID e1374, 2014. View at Publisher · View at Google Scholar · View at Scopus
  103. A. Eskilsson, E. Mirrasekhian, S. Dufour, M. Schwaninger, D. Engblom, and A. Blomqvist, “Immune-induced fever is mediated by IL-6 receptors on brain endothelial cells coupled to STAT3-dependent induction of brain endothelial prostaglandin synthesis,” The Journal of Neuroscience, vol. 34, no. 48, pp. 15957–15961, 2014. View at Publisher · View at Google Scholar · View at Scopus
  104. L. Malmsten, S. Vijayaraghavan, O. Hovatta, A. Marutle, and T. Darreh-Shori, “Fibrillar β-amyloid 1-42 alters cytokine secretion, cholinergic signalling and neuronal differentiation,” Journal of Cellular and Molecular Medicine, vol. 18, no. 9, pp. 1874–1888, 2014. View at Publisher · View at Google Scholar · View at Scopus
  105. L. M. Qin, R. Bouchard, and S. Pugazhenthi, “Regulation of cyclic AMP response element-binding protein during neuroglial interactions,” Journal of Neurochemistry, vol. 136, no. 5, pp. 918–930, 2016. View at Publisher · View at Google Scholar · View at Scopus
  106. M. Rios, “BDNF and the central control of feeding: accidental bystander or essential player?” Trends in Neurosciences, vol. 36, no. 2, pp. 83–90, 2013. View at Publisher · View at Google Scholar · View at Scopus
  107. J. C. Han, M. J. Muehlbauer, H. N. Cui, C. B. Newgard, and A. M. Haqq, “Lower brain-derived neurotrophic factor in patients with Prader-Willi syndrome compared to obese and lean control subjects,” The Journal of Clinical Endocrinology & Metabolism, vol. 95, no. 7, pp. 3532–3536, 2010. View at Publisher · View at Google Scholar · View at Scopus
  108. F. Vanevski and B. Xu, “Molecular and neural bases underlying roles of BDNF in the control of body weight,” Frontiers in Neuroscience, vol. 7, article 37, pp. 1–9, 2013. View at Publisher · View at Google Scholar · View at Scopus
  109. K. Marosi and M. P. Mattson, “BDNF mediates adaptive brain and body responses to energetic challenges,” Trends in Endocrinology and Metabolism, vol. 25, no. 2, pp. 89–98, 2014. View at Publisher · View at Google Scholar · View at Scopus
  110. A. Benigni, P. Cassis, and G. Remuzzi, “Angiotensin II revisited: new roles in inflammation, immunology and aging,” EMBO Molecular Medicine, vol. 2, no. 7, pp. 247–257, 2010. View at Publisher · View at Google Scholar · View at Scopus
  111. K. Mittal and D. P. Katare, “Shared links between type 2 diabetes mellitus and Alzheimer's disease: a review,” Diabetes & Metabolic Syndrome: Clinical Research & Reviews, 2016. View at Publisher · View at Google Scholar
  112. S. Rosales-Corral, D.-X. Tan, L. Manchester, and R. J. Reiter, “Diabetes and alzheimer disease, two overlapping pathologies with the same background: oxidative stress,” Oxidative Medicine and Cellular Longevity, vol. 2015, Article ID 985845, 14 pages, 2015. View at Publisher · View at Google Scholar · View at Scopus
  113. K. Talbot, H.-Y. Wang, H. Kazi et al., “Demonstrated brain insulin resistance in Alzheimer’s disease patients is associated with IGF-1 resistance, IRS-1 dysregulation, and cognitive decline,” The Journal of Clinical Investigation, vol. 122, no. 4, pp. 1316–1338, 2012. View at Publisher · View at Google Scholar · View at Scopus
  114. T. Miyakawa, “Vascular pathology in Alzheimer’s disease,” Psychogeriatrics, vol. 10, no. 1, pp. 39–44, 2010. View at Publisher · View at Google Scholar · View at Scopus
  115. D. Kapogiannis and M. P. Mattson, “Perturbed energy metabolism and neuronal circuit dysfunction in cognitive impairment,” The Lancet Neurology, vol. 10, no. 2, pp. 187–198, 2011. View at Publisher · View at Google Scholar
  116. R. O. Domínguez, M. A. Pagano, E. R. Marschoff, S. E. González, M. G. Repetto, and J. A. Serra, “Alzheimer disease and cognitive impairment associated with diabetes mellitus type 2: associations and a hypothesis,” Neurologia, vol. 29, no. 9, pp. 567–572, 2014. View at Publisher · View at Google Scholar · View at Scopus
  117. E. Calvo-Ochoa and C. Arias, “Cellular and metabolic alterations in the hippocampus caused by insulin signalling dysfunction and its association with cognitive impairment during aging and Alzheimer’s disease: studies in animal models,” Diabetes/Metabolism Research and Reviews, vol. 31, no. 1, pp. 1–13, 2015. View at Publisher · View at Google Scholar · View at Scopus
  118. A. Kleinridders, W. Cai, L. Cappellucci et al., “Insulin resistance in brain alters dopamine turnover and causes behavioral disorders,” Proceedings of the National Academy of Sciences of the United States of America, vol. 112, no. 11, pp. 3463–3468, 2015. View at Publisher · View at Google Scholar · View at Scopus
  119. D. Nuzzo, P. Picone, S. Baldassano et al., “Insulin resistance as common molecular denominator linking obesity to Alzheimer’s disease,” Current Alzheimer Research, vol. 12, no. 8, pp. 723–735, 2015. View at Publisher · View at Google Scholar · View at Scopus
  120. E. S. Chan, C. Chen, G. M. Cole, and B.-S. Wong, “Differential interaction of Apolipoprotein-E isoforms with insulin receptors modulates brain insulin signaling in mutant human amyloid precursor protein transgenic mice,” Scientific Reports, vol. 5, Article ID 13842, 2015. View at Publisher · View at Google Scholar · View at Scopus
  121. D. K. Shoemark and S. J. Allen, “The microbiome and disease: reviewing the links between the oral microbiome, aging, and Alzheimer’s disease,” Journal of Alzheimer’s Disease, vol. 43, no. 3, pp. 725–738, 2015. View at Publisher · View at Google Scholar · View at Scopus
  122. J. Qin, Y. Li, Z. Cai et al., “A metagenome-wide association study of gut microbiota in type-2 diabetes,” Nature, vol. 490, pp. 55–60, 2012. View at Publisher · View at Google Scholar
  123. F. Scheperjan, “Can microbiota research change our understanding of neurodegenerative diseases?” Neurodegenerative Disease Management, vol. 6, no. 2, pp. 81–85, 2016. View at Publisher · View at Google Scholar
  124. P. Maheshwari and G. D. Eslick, “Bacterial infection and Alzheimer’s disease: a meta-analysis,” Journal of Alzheimer’s Disease, vol. 43, no. 3, pp. 957–966, 2015. View at Publisher · View at Google Scholar · View at Scopus
  125. R. Mancuso, F. Baglio, M. Cabinio et al., “Titers of herpes simplex virus type 1 antibodies positively correlate with grey matter volumes in Alzheimer’s disease,” Journal of Alzheimer’s Disease, vol. 38, no. 4, pp. 741–745, 2014. View at Publisher · View at Google Scholar · View at Scopus
  126. R. P. Friedland, “Mechanisms of molecular mimicry involving the microbiota in neurodegeneration,” Journal of Alzheimer’s Disease, vol. 45, no. 2, pp. 349–362, 2015. View at Publisher · View at Google Scholar · View at Scopus
  127. C. M. Lema Tomé, T. Tyson, N. L. Rey, S. Grathwohl, M. Britschgi, and P. Brundin, “Inflammation and α-synuclein’s prion-like behavior in Parkinson’s disease—is there a link?” Molecular neurobiology, vol. 47, no. 2, pp. 561–574, 2013. View at Publisher · View at Google Scholar · View at Scopus
  128. G. Pérez Martínez, C. Bäuerl, and M. C. Collado, “Understanding gut microbiota in elderly’s health will enable intervention through probiotics,” Beneficial Microbes, vol. 5, no. 3, pp. 235–246, 2014. View at Publisher · View at Google Scholar · View at Scopus
  129. M. C. Collado, C. Bäueri, and G. Pérez-Martínez, “Defining microbiota for developing new probiotics,” Microbial Ecology in Health and Disease, vol. 23, pp. 35–39, 2012. View at Google Scholar
  130. A. R. Kamer, R. G. Craig, E. Pirraglia et al., “TNF-α and antibodies to periodontal bacteria discriminate between Alzheimer’s disease patients and normal subjects,” Journal of Neuroimmunology, vol. 216, no. 1-2, pp. 92–97, 2009. View at Publisher · View at Google Scholar · View at Scopus
  131. A. Kumar, C. M. Nisha, C. Silakari et al., “Current and novel therapeutic molecules and targets in Alzheimer’s disease,” Journal of the Formosan Medical Association, vol. 115, no. 1, pp. 3–10, 2016. View at Publisher · View at Google Scholar · View at Scopus
  132. P. Scheltens, K. Blennow, M. M. Breteler et al., “Alzheimer's disease,” The Lancet, 2016. View at Publisher · View at Google Scholar · View at Scopus
  133. L. Nelson and N. Tabet, “Slowing the progression of Alzheimer’s disease; what works?” Ageing Research Reviews, vol. 23, pp. 193–209, 2015. View at Publisher · View at Google Scholar · View at Scopus
  134. D. Mitsushima, A. Sano, and T. Takahashi, “A cholinergic trigger drives learning-induced plasticity at hippocampal synapses,” Nature Communications, vol. 4, article 2760, 2013. View at Publisher · View at Google Scholar · View at Scopus
  135. D. Puzzo, W. Gulisano, O. Arancio, and A. Palmeri, “The keystone of Alzheimer pathogenesis might be sought in Aβ physiology,” Neuroscience, vol. 307, pp. 26–36, 2015. View at Publisher · View at Google Scholar · View at Scopus
  136. A. Garcia-Osta and C. M. Alberini, “Amyloid beta mediates memory formation,” Learning and Memory, vol. 16, no. 4, pp. 267–272, 2009. View at Publisher · View at Google Scholar · View at Scopus
  137. P. Anand and B. Singh, “A review on cholinesterase inhibitors for Alzheimer’s disease,” Archives of Pharmacal Research, vol. 36, no. 4, pp. 375–399, 2013. View at Publisher · View at Google Scholar · View at Scopus
  138. S. Andrieu, N. Coley, S. Lovestone, P. S. Aisen, and B. Vellas, “Prevention of sporadic Alzheimer’s disease: lessons learned from clinical trials and future directions,” The Lancet Neurology, vol. 14, no. 9, pp. 926–944, 2015. View at Publisher · View at Google Scholar · View at Scopus
  139. J. Godyń, J. Jończyk, D. Panek, and B. Malawska, “Therapeutic strategies for Alzheimer’s disease in clinical trials,” Pharmacological Reports, vol. 68, no. 1, pp. 127–138, 2016. View at Publisher · View at Google Scholar · View at Scopus
  140. J. Folch, D. Petrov, M. Ettcheto et al., “Current research therapeutic strategies for Alzheimer’s disease treatment,” Neural Plasticity, vol. 2016, Article ID 8501693, 15 pages, 2016. View at Publisher · View at Google Scholar · View at Scopus
  141. H. Prentice, J. P. Modi, and J.-Y. Wu, “Mechanisms of neuronal protection against excitotoxicity, endoplasmic reticulum stress, and mitochondrial dysfunction in stroke and neurodegenerative diseases,” Oxidative Medicine and Cellular Longevity, vol. 2015, Article ID 964518, 7 pages, 2015. View at Publisher · View at Google Scholar · View at Scopus
  142. X. Shi, X. Lin, R. Hu, N. Sun, J. Hao, and C. Gao, “Toxicological differences between NMDA receptor antagonists and cholinesterase inhibitors,” American Journal of Alzheimer's Disease and Other Dementias, vol. 31, no. 5, pp. 405–412, 2016. View at Publisher · View at Google Scholar
  143. X. Wang, J. Blanchard, I. Grundke-Iqbal, and K. Iqbal, “Memantine attenuates Alzheimer’s disease-like pathology and cognitive impairment,” PLoS ONE, vol. 10, no. 12, Article ID 0145441, 2015. View at Publisher · View at Google Scholar · View at Scopus
  144. M. Chen, “The maze of APP processing in Alzheimer’s disease: where did we go wrong in reasoning?” Frontiers in Cellular Neuroscience, vol. 9, article 186, pp. 1–10, 2015. View at Publisher · View at Google Scholar · View at Scopus
  145. G. T. Corbett, F. J. Gonzalez, and K. Pahan, “Activation of peroxisome proliferator-activated receptor α stimulates ADAM10-mediated proteolysis of APP,” Proceedings of the National Academy of Sciences of the United States of America, vol. 112, no. 27, pp. 8445–8450, 2015. View at Publisher · View at Google Scholar · View at Scopus
  146. M. Shukla, H. H. Htoo, P. Wintachai et al., “Melatonin stimulates the nonamyloidogenic processing of βaPP through the positive transcriptional regulation of ADAM10 and ADAM17,” Journal of Pineal Research, vol. 58, no. 2, pp. 151–165, 2015. View at Publisher · View at Google Scholar · View at Scopus
  147. A. A. Pimenova, A. Thathiah, B. De Strooper, and I. Tesseur, “Regulation of amyloid precursor protein processing by serotonin signaling,” PLoS ONE, vol. 9, no. 1, Article ID e87014, 2014. View at Publisher · View at Google Scholar · View at Scopus
  148. A. Fragkouli, E. C. Tsilibary, and A. K. Tzinia, “Neuroprotective role of MMP-9 overexpression in the brain of Alzheimer’s 5xFAD mice,” Neurobiology of Disease, vol. 70, pp. 179–189, 2014. View at Publisher · View at Google Scholar · View at Scopus
  149. K. W. Menting and J. A. H. R. Claassen, “β-Secretase inhibitor; a promising novel therapeutic drug in Alzheimer’s disease,” Frontiers in Aging Neuroscience, vol. 6, article 165, 2014. View at Publisher · View at Google Scholar · View at Scopus
  150. O. G. Tatarnikova, M. A. Orlov, and N. V. Bobkova, “Beta-amyloid and Tau-protein: structure, interaction, and prion-like properties,” Biochemistry, vol. 80, no. 13, pp. 1800–1819, 2015. View at Publisher · View at Google Scholar · View at Scopus
  151. A. M. Weissmiller, O. Natera-Naranjo, S. M. Reyna et al., “A γ-secretase inhibitor, but not a γ-secretase modulator, induced defects in BDNF axonal trafficking and signaling: evidence for a role for APP,” PLoS ONE, vol. 10, no. 2, Article ID e0118379, 2015. View at Publisher · View at Google Scholar · View at Scopus
  152. K. Takeo, N. Watanabe, T. Tomita, and T. Iwatsubo, “Contribution of the γ-secretase subunits to the formation of catalytic pore of presenilin 1 protein,” The Journal of Biological Chemistry, vol. 287, no. 31, pp. 25834–25843, 2012. View at Publisher · View at Google Scholar · View at Scopus
  153. K. Takeo, S. Tanimura, T. Shinoda et al., “Allosteric regulation of γ-secretase activity by a phenylimidazole-type γ-secretase modulator,” Proceedings of the National Academy of Sciences of the United States of America, vol. 111, no. 29, pp. 10544–10549, 2014. View at Publisher · View at Google Scholar · View at Scopus
  154. J. I. Jung, A. R. Price, T. B. Ladd et al., “Cholestenoic acid, an endogenous cholesterol metabolite, is a potent γ-secretase modulator,” Molecular Neurodegeneration, vol. 10, article 29, 2015. View at Publisher · View at Google Scholar · View at Scopus
  155. M. Awasthi, S. Singh, V. P. Pandey, and U. N. Dwivedi, “Alzheimer’s disease: an overview of amyloid beta dependent pathogenesis and its therapeutic implications along with in silico approaches emphasizing the role of natural products,” Journal of the Neurological Sciences, vol. 361, pp. 256–271, 2016. View at Publisher · View at Google Scholar · View at Scopus
  156. J. Kalra and A. Khan, “Reducing Aβ load and tau phosphorylation: emerging perspective for treating Alzheimer’s disease,” European Journal of Pharmacology, vol. 764, pp. 571–581, 2015. View at Publisher · View at Google Scholar · View at Scopus
  157. A. Francioso, P. Punzi, A. Boffi et al., “β-Sheet interfering molecules acting against β-amyloid aggregation and fibrillogenesis,” Bioorganic and Medicinal Chemistry, vol. 23, no. 8, pp. 1671–1683, 2015. View at Publisher · View at Google Scholar · View at Scopus
  158. M. Han, Y. Liu, Q. Tan et al., “Therapeutic efficacy of stemazole in a beta-amyloid injection rat model of Alzheimer’s disease,” European Journal of Pharmacology, vol. 657, no. 1–3, pp. 104–110, 2011. View at Publisher · View at Google Scholar · View at Scopus
  159. C. Stack, S. Jainuddin, C. Elipenahli et al., “Methylene blue upregulates Nrf2/ARE genes and prevents tau-related neurotoxicity,” Human Molecular Genetics, vol. 23, no. 14, Article ID ddu080, pp. 3716–3732, 2014. View at Publisher · View at Google Scholar · View at Scopus
  160. V. Melis, M. Magbagbeolu, J. E. Rickard et al., “Effects of oxidized and reduced forms of methylthioninium in two transgenic mouse tauopathy models,” Behavioural Pharmacology, vol. 26, no. 4, pp. 353–368, 2015. View at Publisher · View at Google Scholar · View at Scopus
  161. B. Bulic, M. Pickhardt, E.-M. Mandelkow, and E. Mandelkow, “Tau protein and tau aggregation inhibitors,” Neuropharmacology, vol. 59, no. 4-5, pp. 276–289, 2010. View at Publisher · View at Google Scholar · View at Scopus
  162. H. K. I. Dias, C. L. R. Brown, M. C. Polidori, G. Y. H. Lip, and H. R. Griffiths, “LDL-lipids from patients with hypercholesterolaemia and Alzheimer’s disease are inflammatory to microvascular endothelial cells: mitigation by statin intervention,” Clinical Science, vol. 129, no. 12, pp. 1195–1206, 2016. View at Publisher · View at Google Scholar · View at Scopus
  163. F. C. Lin, Y. S. Chuang, H. M. Hsieh et al., “Early statin use and the progression of Alzheimer disease: a total population-based case-control study,” Medicine, vol. 94, no. 47, Article ID e2143, 2015. View at Publisher · View at Google Scholar
  164. S. M. Grundy, “Metabolic syndrome update,” Trends in Cardiovascular Medicine, vol. 26, no. 4, pp. 364–373, 2016. View at Publisher · View at Google Scholar
  165. K. Srikanthan, A. Feyh, H. Visweshwar, J. I. Shapiro, and K. Sodhi, “Systematic review of metabolic syndrome biomarkers: a panel for early detection, management, and risk stratification in the West Virginian population,” International Journal of Medical Sciences, vol. 13, no. 1, pp. 25–38, 2016. View at Publisher · View at Google Scholar · View at Scopus
  166. B. McGuinness, D. Craig, R. Bullock, and P. Passmore, “Statins for the prevention of dementia,” The Cochrane Database of Systematic Reviews, no. 2, Article ID CD003160, 2009. View at Publisher · View at Google Scholar
  167. K. Fukui, H. A. Ferris, and C. R. Kahn, “Effect of cholesterol reduction on receptor signaling in neurons,” The Journal of Biological Chemistry, vol. 290, no. 44, pp. 26383–26392, 2015. View at Publisher · View at Google Scholar · View at Scopus
  168. V. Rani, G. Deep, R. K. Singh, K. Palle, and U. C. S. Yadav, “Oxidative stress and metabolic disorders: pathogenesis and therapeutic strategies,” Life Sciences, vol. 148, no. 11, pp. 183–193, 2016. View at Publisher · View at Google Scholar · View at Scopus
  169. L. M. Waite, “Treatment for Alzheimer’s disease: has anything changed?” Australian Prescriber, vol. 38, no. 2, pp. 60–63, 2015. View at Publisher · View at Google Scholar · View at Scopus
  170. M. K. Jedrziewski, D. C. Ewbank, H. Wang, and J. Q. Trojanowski, “The impact of exercise, cognitive activities, and socialization on cognitive function: results from the national long-term care survey,” American Journal of Alzheimer’s Disease & Other Dementias, vol. 29, no. 4, pp. 372–378, 2014. View at Publisher · View at Google Scholar · View at Scopus
  171. O. C. Okonkwo, S. A. Schultz, J. M. Oh et al., “Physical activity attenuates age-related biomarker alterations in preclinical AD,” Neurology, vol. 83, no. 19, pp. 1753–1760, 2014. View at Publisher · View at Google Scholar · View at Scopus
  172. J. Verghese, R. B. Lipton, M. J. Katz et al., “Leisure activities and the risk of dementia in the elderly,” The New England Journal of Medicine, vol. 348, no. 25, pp. 2508–2516, 2003. View at Publisher · View at Google Scholar · View at Scopus
  173. Y.-H. Sung, “Effects of treadmill exercise on hippocampal neurogenesis in an MPTP /probenecid-induced Parkinson’s disease mouse model,” Journal of Physical Therapy Science, vol. 27, no. 10, pp. 3203–3206, 2015. View at Publisher · View at Google Scholar · View at Scopus
  174. M. S. Nokia, S. Lensu, J. P. Ahtiainen et al., “Physical exercise increases adult hippocampal neurogenesis in male rats provided it is aerobic and sustained,” The Journal of Physiology, vol. 594, no. 7, pp. 1855–1873, 2016. View at Publisher · View at Google Scholar
  175. R. B. Speisman, A. Kumar, A. Rani, T. C. Foster, and B. K. Ormerod, “Daily exercise improves memory, stimulates hippocampal neurogenesis and modulates immune and neuroimmune cytokines in aging rats,” Brain, Behavior, and Immunity, vol. 28, pp. 25–43, 2013. View at Publisher · View at Google Scholar · View at Scopus
  176. T. Paillard, Y. Rolland, and P. S. de Barreto, “Protective effects of physical exercise in Alzheimer’s disease and Parkinson’s disease: a narrative review,” Journal of Clinical Neurology, vol. 11, no. 3, pp. 212–219, 2015. View at Publisher · View at Google Scholar · View at Scopus
  177. P. Bekinschtein, C. A. Oomen, L. M. Saksida, and T. J. Bussey, “Effects of environmental enrichment and voluntary exercise on neurogenesis, learning and memory, and pattern separation: BDNF as a critical variable?” Seminars in Cell & Developmental Biology, vol. 22, no. 5, pp. 536–542, 2011. View at Publisher · View at Google Scholar · View at Scopus
  178. M. P. Mattson, “Lifelong brain health is a lifelong challenge. From evolutionary principles to empirical evidence,” Ageing Research Reviews, vol. 20, pp. 37–45, 2015. View at Publisher · View at Google Scholar · View at Scopus
  179. M. J. Schafer, M. J. Alldred, S. H. Lee et al., “Reduction of β-amyloid and γ-secretase by calorie restriction in female Tg2576 mice,” Neurobiology of Aging, vol. 36, no. 3, pp. 1293–1302, 2015. View at Publisher · View at Google Scholar · View at Scopus
  180. L. Fratiglioni, S. Paillard-Borg, and B. Winblad, “An active and socially integrated lifestyle in late life might protect against dementia,” The Lancet Neurology, vol. 3, no. 6, pp. 343–353, 2004. View at Publisher · View at Google Scholar · View at Scopus
  181. J. A. García-Casal, A. Loizeau, E. Csipke, M. Franco-Martín, M. V. Perea-Bartolomé, and M. Orrell, “Computer-based cognitive interventions for people living with dementia: a systematic literature review and meta-analysis,” Aging & Mental Health, 2016. View at Publisher · View at Google Scholar · View at Scopus
  182. T. Kishi and K. Sunagawa, “Exercise training plus calorie restriction causes synergistic protection against cognitive decline via up-regulation of BDNF in hippocampus of stroke-prone hypertensive rats,” in Proceedings of the 34th Annual International Conference of the IEEE Engineering in Medicine and Biology Society (EMBS ’12), pp. 6764–6767, San Diego, Calif, USA, August 2012. View at Publisher · View at Google Scholar · View at Scopus
  183. Y. Kida and M. S. Goligorsky, “Sirtuins, cell senescence, and vascular aging,” Canadian Journal of Cardiology, vol. 32, no. 5, pp. 634–641, 2016. View at Publisher · View at Google Scholar
  184. I. Amigo and A. J. Kowaltowski, “Dietary restriction in cerebral bioenergetics and redox state,” Redox Biology, vol. 2, no. 1, pp. 296–304, 2014. View at Publisher · View at Google Scholar · View at Scopus
  185. E. J. Dhurandhar, D. B. Allison, T. van Groen, and I. Kadish, “Hunger in the absence of caloric restriction improves cognition and attenuates alzheimer’s disease pathology in a mouse model,” PLoS ONE, vol. 8, no. 4, Article ID e60437, 2013. View at Publisher · View at Google Scholar · View at Scopus
  186. R. Mushtaq, S. Shoib, T. Shah, and S. Mushtaq, “Relationship between loneliness, psychiatric disorders and physical health ? A review on the psychological aspects of loneliness,” Journal of Clinical and Diagnostic Research, vol. 8, no. 9, pp. WE01–WE04, 2014. View at Publisher · View at Google Scholar · View at Scopus
  187. C. A. de Jager, A. Oulhaj, R. Jacoby, H. Refsum, and A. D. Smith, “Cognitive and clinical outcomes of homocysteine-lowering B-vitamin treatment in mild cognitive impairment: a randomized controlled trial,” International Journal of Geriatric Psychiatry, vol. 27, no. 6, pp. 592–600, 2012. View at Publisher · View at Google Scholar · View at Scopus
  188. H. Kim, G. Kim, W. Jang, S. Y. Kim, and N. Chang, “Association between intake of B vitamins and cognitive function in elderly Koreans with cognitive impairment,” Nutrition Journal, vol. 13, no. 1, article 118, pp. 1–11, 2014. View at Publisher · View at Google Scholar
  189. Y. Sun, C.-J. Lu, K.-L. Chien, S.-T. Chen, and R.-C. Chen, “Efficacy of multivitamin supplementation containing vitamins b6 and b12 and folic acid as adjunctive treatment with a cholinesterase inhibitor in Alzheimer’s disease: a 26-week, randomized, double-blind, placebo-controlled study in Taiwanese Patients,” Clinical Therapeutics, vol. 29, no. 10, pp. 2204–2214, 2007. View at Publisher · View at Google Scholar · View at Scopus
  190. A. H. Ford, L. Flicker, H. Alfonso et al., “Vitamins B12, B6, and folic acid for cognition in older men,” Neurology, vol. 75, no. 17, pp. 1540–1547, 2010. View at Publisher · View at Google Scholar · View at Scopus
  191. R. C. Petersen, R. G. Thomas, M. Grundman et al., “Vitamin E and donepezil for the treatment of mild cognitive impairment,” The New England Journal of Medicine, vol. 352, no. 23, pp. 2379–2388, 2005. View at Publisher · View at Google Scholar · View at Scopus
  192. S. Arlt, T. Müller-Thomsen, U. Beisiegel, and A. Kontush, “Effect of one-year vitamin C- and E-supplementation on cerebrospinal fluid oxidation parameters and clinical course in Alzheimer’s disease,” Neurochemical Research, vol. 37, no. 12, pp. 2706–2714, 2012. View at Publisher · View at Google Scholar · View at Scopus
  193. A. K. Gangwar, A. Rawat, S. Tiwari, S. C. Tiwari, J. Narayan, and S. Tiwari, “Role of Vitamin-D in the prevention and treatment of Alzheimer’s disease,” Indian Journal of Physiology and Pharmacology, vol. 59, no. 1, pp. 94–99, 2015. View at Google Scholar · View at Scopus
  194. J. L. Barranco-Quintana, M. F. Allam, A. S. Del Castillo, and R. F. Navajas, “Risk factors for Alzheimer’s disease,” Revue Neurologique, vol. 40, no. 10, pp. 613–618, 2005. View at Google Scholar
  195. A. Giacosa, A. F. Adam-Blondon, S. Baer-Sinnott et al., “Alcohol and wine in relation to cancer and other diseases,” European Journal of Cancer Prevention, vol. 21, no. 1, pp. 103–108, 2012. View at Publisher · View at Google Scholar · View at Scopus
  196. D. Cutuli, P. De Bartolo, P. Caporali et al., “n-3 polyunsaturated fatty acids supplementation enhances hippocampal functionality in aged mice,” Frontiers in Aging Neuroscience, vol. 6, article 220, pp. 1–17, 2014. View at Publisher · View at Google Scholar · View at Scopus
  197. H. Nasri, A. Baradaran, H. Shirzad, and M. Rafeian-Kopaei, “New concepts in nutraceuticals as alternative for pharmaceuticals,” International Journal of Preventive Medicine, vol. 5, no. 12, pp. 1487–1499, 2014. View at Google Scholar · View at Scopus
  198. F. I. Baptista, A. G. Henriques, A. M. S. Silva, J. Wiltfang, and O. A. B. da Cruz E Silva, “Flavonoids as therapeutic compounds targeting key proteins involved in Alzheimer’s disease,” ACS Chemical Neuroscience, vol. 5, no. 2, pp. 83–92, 2014. View at Publisher · View at Google Scholar · View at Scopus
  199. I. Solanki, P. Parihar, M. L. Mansuri, and M. S. Parihar, “Flavonoid-based therapies in the early management of neurodegenerative diseases,” Advances in Nutrition, vol. 6, no. 1, pp. 64–72, 2015. View at Publisher · View at Google Scholar · View at Scopus
  200. M. P. Corcoran, D. L. McKay, and J. B. Blumberg, “Flavonoid basics: chemistry, sources, mechanisms of action, and safety,” Journal of Nutrition in Gerontology and Geriatrics, vol. 31, no. 3, pp. 176–189, 2012. View at Publisher · View at Google Scholar · View at Scopus
  201. G. Desideri, C. Kwik-Uribe, D. Grassi et al., “Benefits in cognitive function, blood pressure, and insulin resistance through cocoa flavanol consumption in elderly subjects with mild cognitive impairment: the Cocoa, Cognition, and Aging (CoCoA) study,” Hypertension, vol. 60, no. 3, pp. 794–801, 2012. View at Publisher · View at Google Scholar · View at Scopus
  202. H. B. Boudouda, A. Zaghib, A. Karioti et al., “Antibacterial, antioxidant, anti-cholinesterase potential and flavonol glycosides of Biscutella raphanifolia (Brassicaceae),” Pakistan Journal of Pharmaceutical Sciences, vol. 28, no. 1, pp. 153–158, 2015. View at Google Scholar
  203. T. Y. Lin, C. W. Lu, C. C. Chang, S. K. Huang, and S. J. Wang, “Luteolin inhibits the release of glutamate in rat cerebrocortical nerve terminals,” Journal of Agricultural and Food Chemistry, vol. 59, no. 15, pp. 8458–8466, 2011. View at Publisher · View at Google Scholar · View at Scopus
  204. J. A. Baur and D. A. Sinclair, “Therapeutic potential of resveratrol: the in vivo evidence,” Nature Reviews Drug Discovery, vol. 5, no. 6, pp. 493–506, 2006. View at Publisher · View at Google Scholar · View at Scopus
  205. T. Ma, M.-S. Tan, J.-T. Yu, and L. Tan, “Resveratrol as a therapeutic agent for Alzheimer’s disease,” BioMed Research International, vol. 2014, Article ID 350516, 13 pages, 2014. View at Publisher · View at Google Scholar
  206. G. T. Diaz-Gerevini, G. Repossi, A. Dain, M. C. Tarres, U. N. Das, and A. R. Eynard, “Beneficial action of resveratrol: how and why?” Nutrition, vol. 32, no. 2, pp. 174–178, 2016. View at Publisher · View at Google Scholar · View at Scopus
  207. Y. A. Kim, G.-Y. Kim, K.-Y. Park, and Y. H. Choi, “Resveratrol inhibits nitric oxide and prostaglandin E2 production by lipopolysaccharide-activated C6 microglia,” Journal of Medicinal Food, vol. 10, no. 2, pp. 218–224, 2007. View at Publisher · View at Google Scholar
  208. S. Bastianetto, C. Ménard, and R. Quirion, “Neuroprotective action of resveratrol,” Biochimica et Biophysica Acta (BBA)—Molecular Basis of Disease, vol. 1852, no. 6, pp. 1195–1201, 2015. View at Publisher · View at Google Scholar · View at Scopus
  209. J. Chen, Y. Zhou, S. Mueller-Steiner et al., “SIRT1 protects against microglia-dependent amyloid-β toxicity through inhibiting NF-κB signaling,” The Journal of Biological Chemistry, vol. 280, no. 48, pp. 40364–40374, 2005. View at Publisher · View at Google Scholar · View at Scopus
  210. J. A. Godoy, J. A. Rios, J. M. Zolezzi, N. Braidy, and N. C. Inestrosa, “Signaling pathway cross talk in Alzheimer’s disease,” Cell Communication and Signaling, vol. 12, article 23, 2014. View at Publisher · View at Google Scholar
  211. D. Y. Yoo, J. H. Choi, W. Kim et al., “Effects of luteolin on spatial memory, cell proliferation, and neuroblast differentiation in the hippocampal dentate gyrus in a scopolamine-induced amnesia model,” Neurological Research, vol. 35, no. 8, pp. 813–820, 2013. View at Publisher · View at Google Scholar · View at Scopus
  212. M. Zhu, D. Chen, D. Li et al., “Luteolin inhibits angiotensin II-induced human umbilical vein endothelial cell proliferation and migration through downregulation of src and Akt phosphorylation,” Circulation Journal, vol. 77, no. 3, pp. 772–779, 2013. View at Publisher · View at Google Scholar · View at Scopus
  213. M. López-Lázaro, “Distribution and biological activities of the flavonoid luteolin,” Mini-Reviews in Medicinal Chemistry, vol. 9, no. 1, pp. 31–59, 2009. View at Publisher · View at Google Scholar · View at Scopus
  214. F. Casamenti, C. Grossi, S. Rigacci, D. Pantano, I. Luccarini, and M. Stefani, “Oleuropein aglycone: a possible drug against degenerative conditions. In vivo evidence of its effectiveness against Alzheimer’s disease,” Journal of Alzheimer’s Disease, vol. 45, no. 3, pp. 679–688, 2015. View at Publisher · View at Google Scholar · View at Scopus
  215. H. I. H. El-Sayyad, “Cholesterol overload impairing cerebellar function: the promise of natural products,” Nutrition, vol. 31, no. 5, pp. 621–630, 2015. View at Publisher · View at Google Scholar · View at Scopus
  216. A. Safouris, G. Tsivgoulis, T. N. Sergentanis, and T. Psaltopoulou, “Mediterranean diet and risk of dementia,” Current Alzheimer Research, vol. 12, no. 8, pp. 736–744, 2015. View at Publisher · View at Google Scholar · View at Scopus
  217. M. Baumgart, H. M. Snyder, M. C. Carrillo, S. Fazio, H. Kim, and H. Johns, “Summary of the evidence on modifiable risk factors for cognitive decline and dementia: a population-based perspective,” Alzheimer’s and Dementia, vol. 11, no. 6, pp. 718–726, 2015. View at Publisher · View at Google Scholar · View at Scopus
  218. N. Hu, J.-T. Yu, L. Tan, Y.-L. Wang, L. Sun, and L. Tan, “Nutrition and the risk of Alzheimer’s disease,” BioMed Research International, vol. 2013, Article ID 524820, 12 pages, 2013. View at Publisher · View at Google Scholar · View at Scopus
  219. S. H. Duncan and H. J. Flint, “Probiotics and prebiotics and health in ageing populations,” Maturitas, vol. 75, no. 1, pp. 44–50, 2013. View at Publisher · View at Google Scholar · View at Scopus
  220. C.-S. Lin, C.-J. Chang, C.-C. Lu et al., “Impact of the gut microbiota, prebiotics, and probiotics on human health and disease,” Biomedical Journal, vol. 37, no. 5, pp. 259–268, 2014. View at Publisher · View at Google Scholar · View at Scopus
  221. J. Liu, J. Sun, F. Wang et al., “Neuroprotective effects of Clostridium butyricum against vascular dementia in mice via metabolic butyrate,” BioMed Research International, vol. 2015, Article ID 412946, 12 pages, 2015. View at Publisher · View at Google Scholar · View at Scopus
  222. D. Prescott, J. Lee, and D. J. Philpott, “An epithelial armamentarium to sense the microbiota,” Seminars in Immunology, vol. 25, no. 5, pp. 323–333, 2013. View at Publisher · View at Google Scholar · View at Scopus
  223. G. Divyashri, G. Krishna, Muralidhara, and S. G. Prapulla, “Probiotic attributes, antioxidant, anti-inflammatory and neuromodulatory effects of Enterococcus faecium CFR 3003: in vitro and in vivo evidence,” Journal of Medical Microbiology, vol. 64, no. 12, pp. 1527–1540, 2015. View at Publisher · View at Google Scholar · View at Scopus
  224. W.-H. Liu, H.-L. Chuang, Y.-T. Huang et al., “Alteration of behavior and monoamine levels attributable to Lactobacillus plantarum PS128 in germ-free mice,” Behavioural Brain Research, vol. 298, pp. 202–209, 2016. View at Publisher · View at Google Scholar · View at Scopus