Molecular Neurobiology

, Volume 54, Issue 8, pp 6471–6489 | Cite as

Middle-Aged Diabetic Females and Males Present Distinct Susceptibility to Alzheimer Disease-like Pathology

  • E. Candeias
  • A. I. Duarte
  • I. Sebastião
  • M. A. Fernandes
  • A. I. Plácido
  • C. Carvalho
  • S. Correia
  • R. X. Santos
  • R. Seiça
  • M. S. Santos
  • C. R. Oliveira
  • P. I. Moreira
Article

Abstract

Type 2 diabetes (T2D) is a highly concerning public health problem of the twenty-first century. Currently, it is estimated that T2D affects 422 million people worldwide with a rapidly increasing prevalence. During the past two decades, T2D has been widely shown to have a major impact in the brain. This, together with the cognitive decline and increased risk for dementia upon T2D, may arise from the complex interaction between normal brain aging and central insulin signaling dysfunction. Among the several features shared between T2D and some neurodegenerative disorders (e.g., Alzheimer disease (AD)), the impairment of insulin signaling may be a key link. However, these may also involve changes in sex hormones’ function and metabolism, ultimately contributing to the different susceptibilities between females and males to some pathologies. For example, female sex has been pointed as a risk factor for AD, particularly after menopause. However, less is known on the underlying molecular mechanisms or even if these changes start during middle-age (perimenopause). From the above, we hypothesized that sex differentially affects hormone-mediated intracellular signaling pathways in T2D brain, ultimately modulating the risk for neurodegenerative conditions. We aimed to evaluate sex-associated alterations in estrogen/insulin-like growth factor-1 (IGF-1)/insulin-related signaling, oxidative stress markers, and AD-like hallmarks in middle-aged control and T2D rat brain cortices. We used brain cortices homogenates obtained from middle-aged (8-month-old) control Wistar and non-obese, spontaneously T2D Goto-Kakizaki (GK) male and female rats. Peripheral characterization of the animal models was done by standard biochemical analyses of blood, plasma, or serum. Steroid sex hormones, oxidative stress markers, and AD-like hallmarks were given by specific ELISA kits and colorimetric techniques, whereas the levels of intracellular signaling proteins were determined by Western blotting. Albeit the high levels of plasma estradiol and progesterone observed in middle-aged control females suggested that they were still under their reproductive phase, some gonadal dysfunction might be already occurring in T2D ones, hence, anticipating their menopause. Moreover, the higher blood and lower brain cholesterol levels in female rats suggested that its dysfunctional uptake into the brain cortex may also hamper peripheral estrogen uptake and/or its local brain steroidogenic metabolism. Despite the massive drop in IGF-1 levels in females’ brains, particularly upon T2D, they might have developed some compensatory mechanisms towards the maintenance of estrogen, IGF-1, and insulin receptors function and of the subsequent Akt- and ERK1/2-mediated signaling. These may ultimately delay the deleterious AD-like brain changes (including oxidative damage to lipids and DNA, amyloidogenic processing of amyloid precursor protein and increased tau protein phosphorylation) associated with T2D and/or age (reproductive senescence) in female rats. By demonstrating that differential sex steroid hormone profiles/action may play a pivotal role in brain over T2D progression, the present study reinforces the need to establish sex-specific preventive and/or therapeutic approaches and an appropriate time window for the efficient treatment against T2D and AD.

Keywords

Sex Type 2 diabetes Alzheimer disease-like hallmarks Insulin Sex steroids 

References

  1. 1.
    NCD Risk Factor Collaboration (NCD-RisC) (2016) Worldwide trends in diabetes since 1980: a pooled analysis of 751 population-based studies with 4.4 million participants. Lancet. doi:10.1016/S0140-6736(16)00618-8 Google Scholar
  2. 2.
    World health statistics 2015 (2015) World Health Organization (WHO). http://apps.who.int/iris/bitstream/10665/170250/1/9789240694439_eng.pdf?ua=1&ua=1. Accessed 23 May 2016
  3. 3.
    Maruthur NM (2013) The growing prevalence of type 2 diabetes: increased incidence or improved survival? Curr Diab Rep. doi:10.1007/s11892-013-0426-4 PubMedGoogle Scholar
  4. 4.
    Rouquet T, Bonnet MS, Pierre C, Dallaporta M, Troadec JD, Roux J, Bariohay B (2013) The central question of type 2 diabetes. Pharm Pat Anal. doi:10.4155/ppa.13.22 PubMedGoogle Scholar
  5. 5.
    Duarte AI, Moreira PI, Oliveira CR (2012) Insulin in central nervous system: more than just a peripheral hormone. J Aging Res doi. doi:10.1155/2012/384017 Google Scholar
  6. 6.
    Carvalho C, Correia SC, Santos MS, Baldeiras I, Oliveira CR, Seica R, Moreira PI (2014) Vascular, oxidative, and synaptosomal abnormalities during aging and the progression of type 2 diabetes. Curr Neurovasc Res. doi:10.2174/1567202611666140903122801 Google Scholar
  7. 7.
    De Felice FG, Ferreira ST (2014) Inflammation, defective insulin signaling, and mitochondrial dysfunction as common molecular denominators connecting type 2 diabetes to Alzheimer disease. Diabetes. doi:10.2337/db13-1954 PubMedGoogle Scholar
  8. 8.
    Wang L, Zhai YQ, Xu LL, Qiao C, Sun XL, Ding JH, Lu M, Hu G (2014) Metabolic inflammation exacerbates dopaminergic neuronal degeneration in response to acute MPTP challenge in type 2 diabetes mice. Exp Neurol. doi:10.1016/j.expneurol.2013.11.001 Google Scholar
  9. 9.
    Sima AAF (2010) Encephalopathies: the emerging diabetic complications. Acta Diabetol 47:279–293PubMedCrossRefGoogle Scholar
  10. 10.
    Correia SC, Santos RX, Perry G, Zhu X, Moreira PI et al (2011) Insulin-resistant brain state: the culprit in sporadic Alzheimer’s disease? Ageing Res Rev doi. doi:10.1016/j.arr.2011.01.001 Google Scholar
  11. 11.
    Frisardi V, Solfrizzi V, Capurso C, Imbimbo BP, Vendemiale G, Seripa D, Pilotto A, Panza F (2010) Is insulin resistant brain state a central feature of the metabolic-cognitive syndrome? J Alzheimer Dis. doi:10.3233/JAD-2010-100015 Google Scholar
  12. 12.
    Hölscher C (2014) Central effects of GLP-1: new opportunities for treatments of neurodegenerative diseases. J Endocrinol. doi:10.1530/JOE-13-0221 PubMedGoogle Scholar
  13. 13.
    Sebastião I, Candeias E, Santos MS, de Oliveira CR, Moreira PI, Duarte AI (2014) Insulin as a bridge between type 2 diabetes and Alzheimer disease—how anti-diabetics could be a solution for dementia. Front Endocrinol (Lausanne). doi:10.3389/fendo.2014.00110 Google Scholar
  14. 14.
    Rettberg JR, Yao J, Brinton RD (2014) Estrogen: a master regulator of bioenergetic systems in the brain and body. Front Neuroendocrinol. doi:10.1016/j.yfrne.2013.08.001 PubMedGoogle Scholar
  15. 15.
    Duarte AI, Candeias E, Correia SC, Santos RX, Carvalho C, Cardoso S, Plácido A, Santos MS et al (2013) Crosstalk between diabetes and brain: glucagon-like peptide-1 mimetics as a promising therapy against neurodegeneration. Biochim Biophys Acta. doi:10.1016/j.bbadis.2013.01.008 Google Scholar
  16. 16.
    Hunter K, Hölscher C (2012) Drugs developed to treat diabetes, liraglutide and lixisenatide, cross the blood brain barrier and enhance neurogenesis. BMC Neurosci. doi:10.1186/1471-2202-13-33 PubMedPubMedCentralGoogle Scholar
  17. 17.
    Kautzky-Willer A, Harreiter J, Pacini G (2016) Sex and gender differences in risk, pathophysiology and complications of type 2 diabetes mellitus. Endocr Rev. doi:10.1210/er.2015-1137 PubMedPubMedCentralGoogle Scholar
  18. 18.
    Wändell PE, Carlsson AC (2014) Gender differences and time trends in incidence and prevalence of type 2 diabetes in Sweden—a model explaining the diabetes epidemic worldwide today? Diabetes Res Clin Pract. doi:10.1016/j.diabres.2014.09.013 PubMedGoogle Scholar
  19. 19.
    Grant JF, Hicks N, Taylor AW, Chittleborough CR, Phillips PJ, North West Adelaide Health Study Team (2009) Gender-specific epidemiology of diabetes: a representative cross-sectional study. Int J Equity Health. doi:10.1186/1475-9276-8-6 PubMedPubMedCentralGoogle Scholar
  20. 20.
    Wild S, Roglic G, Green A, Sicree R, King H (2004) Global prevalence of diabetes: estimates for the year 2000 and projections for 2030. Diabetes Care. doi:10.2337/diacare.27.5.1047 PubMedGoogle Scholar
  21. 21.
    Alzheimer’s Association (2016) 2016 Alzheimer’s disease facts and figures. Alzheimers Dement 12(4)Google Scholar
  22. 22.
    Pereira RI, Casey BA, Swibas TA, Erickson CB, Wolfe P, Van Pelt RE (2015) Timing of estradiol treatment after menopause may determine benefit or harm to insulin action. J Clin Endocrinol Metab. doi:10.1210/jc.2015-3084 PubMedCentralGoogle Scholar
  23. 23.
    Arnetz L, Ekberg NR, Alvarsson M (2014) Sex differences in type 2 diabetes: focus on disease course and outcomes. Diabetes Metab Syndr Obes. doi:10.2147/DMSO.S51301 PubMedPubMedCentralGoogle Scholar
  24. 24.
    Davey DA (2013) Alzheimer’s disease, dementia, mild cognitive impairment and the menopause: a ‘window of opportunity’? Women’s Health (London Engl). doi:10.2217/whe.13.22 Google Scholar
  25. 25.
    Hirata-Fukae C, Li HF, Hoe HS, Gray AJ, Minami SS, Hamada K, Niikura T, Hua F et al (2008) Females exhibit more extensive amyloid, but not tau, pathology in an Alzheimer transgenic model. Brain Res. doi:10.1016/j.brainres.2008.03.079 PubMedGoogle Scholar
  26. 26.
    Green PS, Simpkins JW (2000) Estrogens and estrogen-like non-feminizing compounds. Their role in the prevention and treatment of Alzheimer’s disease. Ann N Y Acad Sci. doi:10.1111/j.1749-6632.2000.tb05566.x Google Scholar
  27. 27.
    Bachman DL, Wolf PA, Linn R, Knoefel JE, Cobb J, Belanger A, D’Agostino RB, White LR (1992) Prevalence of dementia and probable senile dementia of the Alzheimer type in the Framingham study. Neurology 42:115–119PubMedCrossRefGoogle Scholar
  28. 28.
    Wang KC, Woung LC, Tsai MT, Liu CC, Su YH, Li CY (2012) Risk of Alzheimer’s disease in relation to diabetes: a population-based cohort study. Neuroepidemiology. doi:10.1159/000337428 Google Scholar
  29. 29.
    Hempel R, Onopa R, Convit A (2012) Type 2 diabetes affects hippocampus volume differentially in men and women. Diabetes Metab Res Rev. doi:10.1002/dmrr.1230 PubMedPubMedCentralGoogle Scholar
  30. 30.
    Sakata A, Mogi M, Iwanami J, Tsukuda K, Min LJ, Jing F, Iwai M, Ito M et al (2010) Female exhibited severe cognitive impairment in type 2 diabetes mellitus mice. Life Sci. doi:10.1016/j.lfs.2010.03.003 Google Scholar
  31. 31.
    Ding J, Strachan MW, Reynolds RM, Frier BM, Deary IJ, Fowkes FG, Lee AJ, McKnight J et al (2010) Diabetic retinopathy and cognitive decline in older people with type 2 diabetes: the Edinburgh type 2 diabetes study. Diabetes. doi:10.2337/db10-0752 Google Scholar
  32. 32.
    Long J, He P, Shen Y, Li R (2012) New evidence of mitochondria dysfunction in the female Alzheimer’s disease brain: deficiency of estrogen receptor-β. J Alzheimers Dis. doi:10.3233/JAD-2012-120283 PubMedPubMedCentralGoogle Scholar
  33. 33.
    López-Grueso R, Borrás C, Gambini J, Viña J (2010) Aging and ovariectomy cause a decrease in brain glucose consumption in vivo in Wistar rats. Rev Esp Geriatr Gerontol. doi:10.1016/j.regg.2009.12.005 PubMedGoogle Scholar
  34. 34.
    Yue X, Lu M, Lancaster T, Cao P, Honda S, Staufenbiel M, Harada N, Zhong Z et al (2005) Brain estrogen deficiency accelerates Abeta plaque formation in an Alzheimer’s disease animal model. Proc Natl Acad Sci U S A. doi:10.1073/pnas.0505203102 Google Scholar
  35. 35.
    Sherwin BB (2003) Estrogen and cognitive functioning in women. Endocr Rev. doi:10.1210/er.2001-0016 PubMedGoogle Scholar
  36. 36.
    Vest RS, Pike CJ (2013) Gender, sex steroids hormones and Alzheimer’s disease. Horm Behav. doi:10.1016/j.yhbeh.2012.04.006 PubMedGoogle Scholar
  37. 37.
    Winkler JM, Fox HS (2013) Transcriptome meta-analysis reveals a central role for sex steroids in the degeneration of hippocampal neurons in Alzheimer’s disease. BMC Syst Biol. doi:10.1186/1752-0509-7-51 PubMedPubMedCentralGoogle Scholar
  38. 38.
    Caruso D, Scurati S, Maschi O, De Angelis L, Roglio I, Giatti S, Garcia-Segura LM, Melcangi RC (2008) Evaluation of neuroactive steroid levels by liquid chromatography–tandem mass spectrometry in central and peripheral nervous system: effect of diabetes. Neurochem Int. doi:10.1016/j.neuint.2007.06.004 PubMedGoogle Scholar
  39. 39.
    Lapchak PA, Araujo DM (2001) Preclinical development of neurosteroids as neuroprotective agents for the treatment of neurodegenerative diseases. Int Rev Neurobiol 46:379–397PubMedCrossRefGoogle Scholar
  40. 40.
    Zhao L, Morgan TE, Mao Z, Lin S, Cadenas E, Finch CE, Pike CJ, Mack WJ et al (2012) Continuous versus cyclic progesterone exposure differentially regulates hippocampal gene expression and functional profiles. PLoS One. doi:10.1371/journal.pone.0031267 Google Scholar
  41. 41.
    Yao J, Irwin RW, Zhao L, Nilsen J, Hamilton RT, Brinton RD (2009) Mitochondrial bioenergetic deficit precedes Alzheimer’s pathology in female mouse model of Alzheimer’s disease. Proc Natl Acad Sci U S A. doi:10.1073/pnas.0903563106 Google Scholar
  42. 42.
    Morán J, Garrido P, Alonso A, Cabello E, González C (2013) 17β-estradiol and genistein acute treatments improve some cerebral cortex homeostasis aspects deteriorated by aging in female rats. Exp Gerontol. doi:10.1016/j.exger.2013.02.010 PubMedGoogle Scholar
  43. 43.
    Alonso A, González-Pardo H, Garrido P, Conejo NM, Llaneza P, Díaz F, Del Rey CG, González C (2010) Acute effects of 17 β-estradiol and genistein on insulin sensitivity and spatial memory in aged ovariectomized female rats. Age (Dordr). doi:10.1007/s11357-010-9148-6 Google Scholar
  44. 44.
    Vikan T, Schirmer H, Njølstad I, Svartberg J (2010) Low testosterone and sex hormone-binding globulin levels and high estradiol levels are independent predictors of type 2 diabetes in men. Eur J Endocrinol. doi:10.1530/EJE-09-0943 PubMedGoogle Scholar
  45. 45.
    Leonelli E, Bianchi R, Cavaletti G, Caruso D, Crippa D, Garcia-Segura LM, Lauria G, Magnaghi V et al (2007) Progesterone and its derivaes are neuroprotective agents in experimental diabetic neuropathy: a multimodal analysis. Neuroscience. doi:10.1016/j.neuroscience.2006.11.014 PubMedGoogle Scholar
  46. 46.
    Oh JY, Barrett-Connor E, Wedick NM, Wingard DL, Rancho Bernardo Study (2002) Endogenous sex hormones and the development of type 2 diabetes in older men and women: the rancho Bernardo study. Diabetes Care. doi:10.2337/diacare.25.1.55 PubMedGoogle Scholar
  47. 47.
    Mitkov MD, Aleksandrova IY, Orbetzova MM (2013) Effect of transdermal testosterone or alpha-lipoic acid on erectile dysfunction and quality of life in patients with type 2 diabetes mellitus. Folia Med (Plovdiv) 55:55–63Google Scholar
  48. 48.
    Muñoz YC, Gomez GI, Moreno M, Solis CL, Valladares LE, Velarde V (2012) Dehydroepiandrosterone prevents the aggregation of platelets obtained from postmenopausal women with type 2 diabetes mellitus through the activation of the PKC/eNOS/NO pathway. Horm Metab Res. doi:10.1055/s-0032-1309056 PubMedGoogle Scholar
  49. 49.
    Saravia FE, Beauquis J, Revsin Y, Homo-Delarche F, de Kloet ER, De Nicola AF (2006) Hippocampal neuropathology of diabetes mellitus is relieved by estrogen treatment. Cell Mol Neurobiol 26:943–957PubMedCrossRefGoogle Scholar
  50. 50.
    Aragno M, Mastrocola R, Brignardello E, Catalano M, Robino G, Manti R, Parola M, Danni O et al (2002) Dehydroepiandrosterone modulates nuclear factor-kappaB activation in hippocampus of diabetic rats. Endocrinology. doi:10.1210/en.2002-220182 PubMedGoogle Scholar
  51. 51.
    Cui J, Jothishankar B, He P, Staufenbiel M, Shen Y, Li R (2014) Amyloid precursor protein mutation disrupts reproductive experience-enhanced normal cognitive development in a mouse model of Alzheimer’s disease. Mol Neurobiol. doi:10.1007/s12035-013-8503-x Google Scholar
  52. 52.
    Pawluski JL, Galea LA (2006) Hippocampal morphology is differentially affected by reproductive experience in the mother. J Neurobiol. doi:10.1002/neu.20194 PubMedGoogle Scholar
  53. 53.
    Love G, Torrey N, McNamara I, Morgan M, Banks M, Hester NW, Glasper ER, Devries AC et al (2005) Maternal experience produces long-lasting behavioral modifications in the rat. Behav Neurosci. doi:10.1037/0735-7044.119.4.1084 PubMedGoogle Scholar
  54. 54.
    Kinsley CH, Madonia L, Gifford GW, Tureski K, Griffin GR, Lowry C, Williams J, Collins J et al (1999) Motherhood improves learning and memory. Nature. doi:10.1038/45957 PubMedGoogle Scholar
  55. 55.
    Santos RX, Correia SC, Alves MG, Oliveira PF, Cardoso S, Carvalho C, Seiça R, Santos MS et al (2014) Mitochondrial quality control systems sustain brain mitochondrial bioenergetics in early stages of type 2 diabetes. Mol Cell Biochem. doi:10.1007/s11010-014-2076-5 Google Scholar
  56. 56.
    Duarte AI, Santos MS, Seiça R, Oliveira CR (2004) Oxidative stress affects synaptosomal gamma-aminobutyric acid and glutamate transport in diabetic rats: the role of insulin. Diabetes. doi:10.2337/diabetes.53.8.2110 PubMedGoogle Scholar
  57. 57.
    Moreira PI, Santos MS, Moreno AM, Seiça R, Oliveira CR (2003) Increased vulnerability of brain mitochondria in diabetic (Goto-Kakizaki) rats with aging and amyloid-beta exposure. Diabetes. doi:10.2337/diabetes.52.6.1449 PubMedGoogle Scholar
  58. 58.
    Santos MS, Duarte AI, Matos MJ, Proença T, Seiça R, Oliveira CR (2000) Synaptosomes isolated from Goto-Kakizaki diabetic rat brain exhibit increased resistance to oxidative stress: role of vitamin E. Life Sci. doi:10.1016/S0024-3205(00)00892-4 Google Scholar
  59. 59.
    Moreira T, Cebers G, Pickering C, Ostenson CG, Efendic S, Liljequist S (2007) Diabetic Goto-Kakizaki rats display pronounced hyperglycemia and longer-lasting cognitive impairments following ischemia induced by cortical compression. Neuroscience. doi:10.1016/j.neuroscience.2006.10.054 PubMedCentralGoogle Scholar
  60. 60.
    Moreira T, Malec E, Ostenson CG, Efendic S, Liljequist S (2007) Diabetic type II Goto-Kakizaki rats show progressively decreasing exploratory activity and learning impairments in fixed and progressive ratios of a lever-press task. Behav Brain Res. doi:10.1016/j.bbr.2007.02.034 PubMedGoogle Scholar
  61. 61.
    Abdul-Rahman O, Sasvari-Szekely M, Ver A, Rosta K, Szasz BK, Kereszturi E, Keszler G (2012) Altered gene expression profiles in the hippocampus and prefrontal cortex of type 2 diabetic rats. BMC Genomics. doi:10.1186/1471-2164-13-81 PubMedPubMedCentralGoogle Scholar
  62. 62.
    Moreira PI, Santos MS, Sena C, Seiça R, Oliveira CR (2005) Insulin protects against amyloid beta-peptide toxicity in brain mitochondria of diabetic rats. Neurobiol Dis. doi:10.1016/j.nbd.2004.10.017 PubMedGoogle Scholar
  63. 63.
    Hussain S, Mansouri S, Sjöholm Å, Patrone C, Darsalia V (2014) Evidence for cortical neuronal loss in male type 2 diabetic Goto-Kakizaki rats. J Alzheimers Dis. doi:10.3233/JAD-131958 PubMedGoogle Scholar
  64. 64.
    Li R, Cui J, Jothishankar B, Shen J, He P, Shen Y (2013) Early reproductive experiences in females make differences in cognitive function later in life. J Alzheimers Dis. doi:10.3233/JAD-122101 Google Scholar
  65. 65.
    Faul F, Erdfelder E, Lang AG, Buchner A (2007) G*power 3: a flexible statistical power analysis program for the social, behavioral, and biomedical sciences. Behav Res Methods 39:175–191PubMedCrossRefGoogle Scholar
  66. 66.
    Matafome P, Louro T, Rodrigues L, Crisóstomo J, Nunes E, Amaral C, Monteiro P, Cipriano A et al (2011) Metformin and atorvastatin combination further protect the liver in type 2 diabetes with hyperlipidaemia. Diabetes Metab Res Rev. doi:10.1002/dmrr.1157 PubMedGoogle Scholar
  67. 67.
    Sedmak JJ, Grossberg SE (1977) A rapid, sensitive, and versatile assay for protein using Coomassie brilliant blue G250. Anal Biochem 79:544–552PubMedCrossRefGoogle Scholar
  68. 68.
    Duarte AI, Santos P, Oliveira CR, Santos MS, Rego AC (2008) Insulin neuroprotection against oxidative stress is mediated by Akt and GSK-3beta signaling pathways and changes in protein expression. Biochim Biophys Acta. doi:10.1016/j.bbamcr.2008.02.016 PubMedGoogle Scholar
  69. 69.
    Ernster L, Nordenbrand K (1967) Microsomal lipid peroxidation. Methods Enzymol 10:574–580CrossRefGoogle Scholar
  70. 70.
    Janssen U, Riley SG, Vassiliadou A, Floege J, Phillips AO (2003) Hypertension superimposed on type II diabetes in Goto Kakizaki rats induces progressive nephropathy. Kidney Int 63:2162–2170PubMedCrossRefGoogle Scholar
  71. 71.
    Galli J, Fakhrai-Rad H, Kamel A, Marcus C, Norgren S, Luthman H (1999) Pathophysiological and genetic characterization of the major diabetes locus in GK rats. Diabetes 48:2463–2470PubMedCrossRefGoogle Scholar
  72. 72.
    Tsutsui K (2012) Neurosteroid biosynthesis and action during cerebellar development. Cerebellum. doi:10.1007/s12311-011-0341-7 Google Scholar
  73. 73.
    Mellon SH, Griffin LD (2002) Neurosteroids: biochemistry and clinical significance. Trends Endocrinol Metab. doi:10.1016/S1043-2760(01)00503-3 PubMedGoogle Scholar
  74. 74.
    Alonso A, Moreno M, Ordóñez P, Fernández R, Pérez C, Díaz F, Navarro A, Tolivia J et al (2008) Chronic estradiol treatment improves brain homeostasis during aging in female rats. Endocrinology. doi:10.1210/en.2007-0627 Google Scholar
  75. 75.
    Montague D, Weickert CS, Tomaskovic-Crook E, Rothmond DA, Kleinmant JE, Rubinow DR (2008) Oestrogen receptor α localisation in the prefrontal cortex of three mammalian species. J Neuroendocrinol. doi:10.1111/j.1365-2826.2008.01743.x PubMedPubMedCentralGoogle Scholar
  76. 76.
    McEwen BS, Alves SH (1999) Estrogen actions in the central nervous system. Endocr Rev. doi:10.1210/edrv.20.3.0365 PubMedGoogle Scholar
  77. 77.
    Zhao L, Yao J, Mao Z, Chen S, Wang Y, Brinton RD (2011) 17β-estradiol regulates insulin-degrading enzyme expression via an ERβ/PI3-K pathway in hippocampus: relevance to Alzheimer’s prevention. Neurobiol Aging. doi:10.1016/j.neurobiolaging.2009.12.010 Google Scholar
  78. 78.
    Rosario ER, Carroll J, Pike CJ (2010) Testosterone regulation of Alzheimer-like neuropathology in male 3xTg-AD mice involves both estrogen and androgen pathways. Brain Res. doi:10.1016/j.brainres.2010.08.068 Google Scholar
  79. 79.
    Cardona-Gomez GP, Mendez P, DonCarlos LL, Azcoitia I, Garcia-Segura LM (2002) Interactions of estrogen and insulin-like growth factor-I in the brain: molecular mechanisms and functional implications. J Steroid Biochem Mol Biol. doi:10.1016/S0960-0760(02)00261-3 PubMedGoogle Scholar
  80. 80.
    Cardona-Gomez GP, Mendez P, Garcia-Segura LM (2002) Synergistic interaction of estradiol and insulin-like growth factor-I in the activation of PI3K/Akt signaling in the adult rat hypothalamus. Brain Res Mol Brain Res. doi:10.1016/S0169-328X(02)00449-7 PubMedGoogle Scholar
  81. 81.
    Patrone C, Ma ZQ, Pollio G, Agrati P, Parker MG, Maggi A (1996) Cross-coupling between insulin and estrogen receptor in human neuroblastoma cells. Mol Endocrinol. doi:10.1210/mend.10.5.8732681 PubMedGoogle Scholar
  82. 82.
    Kato S, Endoh H, Masuhiro Y, Kitamoto T, Uchiyama S, Sasaki H, Masushige S, Gotoh Y et al (1995) Activation of the estrogen receptor through phosphorylation by mitogen-activated protein kinase. Science. doi:10.1126/science.270.5241.1491 Google Scholar
  83. 83.
    Moran C, Phan TG, Chen J, Blizzard L, Beare R, Venn A, Münch G, Wood AG et al (2013) Brain atrophy in type 2 diabetes: regional distribution and influence on cognition. Diabetes Care. doi:10.2337/dc13-0143 PubMedCentralGoogle Scholar
  84. 84.
    Cholerton B, Baker LD, Craft S (2011) Insulin resistance and pathological brain ageing. Diabet Med. doi:10.1111/j.1464-5491.2011.03464.x PubMedGoogle Scholar
  85. 85.
    Garcia-Segura LM, Arevalo MA, Azcoitia I (2010) Interactions of estradiol and insulin-like growth factor-I signalling in the nervous system: new advances. Prog Brain Res. doi:10.1016/S0079-6123(08)81014-X PubMedGoogle Scholar
  86. 86.
    Garcia-Segura LM, Sanz A, Mendez P (2006) Cross-talk between IGF-I and estradiol in the brain: focus on neuroprotection. Neuroendocrinology. doi:10.1159/000097485 PubMedGoogle Scholar
  87. 87.
    Srikanth V, Maczurek A, Phan T, Steele M, Westcott B, Juskiw D, Münch G (2011) Advanced glycation endproducts and their receptor RAGE in Alzheimer’s disease. Neurobiol Aging. doi:10.1016/j.neurobiolaging.2009.04.016 PubMedGoogle Scholar
  88. 88.
    Qiu C, Cotch MF, Sigurdsson S, Garcia M, Klein R, Jonasson F, Klein BE, Eiriksdottir G et al (2008) Retinal and cerebral microvascular signs and diabetes: the age, gene/environment susceptibility-Reykjavik study. Diabetes. doi:10.2337/db07-1455 Google Scholar
  89. 89.
    den Heijer T, Vermeer SE, van Dijk EJ, Prins ND, Koudstaal PJ, Hofman A, Breteler MM (2003) Type 2 diabetes and atrophy of medial temporal lobe structures on brain MRI. Diabetologia. doi:10.1007/s00125-003-1235-0 Google Scholar
  90. 90.
    Matsuzaki T, Sasaki K, Tanizaki Y, Hata J, Fujimi K, Matsui Y, Sekita A, Suzuki SO et al (2010) Insulin resistance is associated with the pathology of Alzheimer disease: the Hisayama study. Neurology. doi:10.1212/WNL.0b013e3181eee25f PubMedGoogle Scholar
  91. 91.
    Augustinack JC, Schneider A, Mandelkow EM, Hyman BT (2002) Specific tau phosphorylation sites correlate with severity of neuronal cytopathology in Alzheimer’s disease. Acta Neuropathol 103:26–35PubMedCrossRefGoogle Scholar
  92. 92.
    Goedert M, Jakes R, Qi Z, Wang JH, Cohen P (1995) Protein phosphatase 2A is the major enzyme in brain that dephosphorylates tau protein phosphorylated by proline-directed protein kinases or cyclic AMP-dependent protein kinase. J Neurochem. doi:10.1046/j.1471-4159.1995.65062804.x PubMedGoogle Scholar
  93. 93.
    Hoffmann R, Lee VMY, Leight S, Varga I, Otvos L Jr (1997) Unique Alzheimer’s disease paired helical filament specific epitopes involve double phosphorylation at specific sites. Biochemistry. doi:10.1021/bi970380+ Google Scholar
  94. 94.
    Martin L, Latypova X, Terro F (2011) Post-translational modifications of tau protein: implications for Alzheimer’s disease. Neurochem Int. doi:10.1016/j.neuint.2010.12.023 PubMedCentralGoogle Scholar
  95. 95.
    Johnson G, Stoothoff W (2004) Tau phosphorylation in neuronal cell function and dysfunction. J Cell Sci. doi:10.1242/jcs.01558 Google Scholar
  96. 96.
    Xing Y, Qin W, Li F, Jia XF, Jia J (2013) Associations between sex hormones and cognitive and neuropsychiatric manifestations in vascular dementia (VaD). Arch Gerontol Geriatr. doi:10.1016/j.archger.2012.10.003 PubMedGoogle Scholar
  97. 97.
    Guarner-Lans V, Rubio-Ruiz ME, Pérez-Torres I, Baños de MacCarthy G (2011) Relation of aging and sex hormones to metabolic syndrome and cardiovascular disease. Exp Gerontol. doi:10.1016/j.exger.2011.02.007 PubMedGoogle Scholar
  98. 98.
    Carroll JC, Rosario ER, Kreimer S, Villamagna A, Gentzschein E, Stanczyk FZ, Pike CJ (2010) Sex differences in β-amyloid accumulation in 3xTg-AD mice: role of neonatal sex steroid hormone exposure. Brain Res. doi:10.1016/j.brainres.2010.10.009 Google Scholar
  99. 99.
    Schäfer S, Wirths O, Multhaup G, Bayer TA (2007) Gender dependent APP processing in a transgenic mouse model of Alzheimer’s disease. J Neural Transm (Vienna). doi:10.1007/s00702-006-0580-9 Google Scholar
  100. 100.
    Tourrel C, Bailbe D, Lacorne M, Meile MJ, Kergoat M, Portha B (2002) Persistent improvement of type 2 diabetes in the Goto-Kakizaki rat model by expansion of the beta-cell mass during the prediabetic period with glucagon-like peptide-1 or exendin-4. Diabetes. doi:10.2337/diabetes.51.5.1443 PubMedGoogle Scholar
  101. 101.
    Movassat J, Saulnier C, Serradas P, Portha B (1997) Impaired development of pancreatic beta-cell mass is a primary event during the progression to diabetes in the GK rat. Diabetologia. doi:10.1007/s001250050768 PubMedGoogle Scholar
  102. 102.
    Movassat J, Calderari S, Fernández E, Martín MA, Escrivá F, Plachot C, Gangnerau MN, Serradas P et al (2007) Type 2 diabetes—a matter of failing beta-cell neogenesis? Clues from the GK rat model. Diabetes Obes Metab. doi:10.1111/j.1463-1326.2007.00786.x PubMedGoogle Scholar
  103. 103.
    Noll C, Lacraz G, Ehses J, Coulaud J, Bailbe D, Paul JL, Portha B, Homo-Delarche F et al (2011) Early reduction of circulating homocysteine levels in Goto-Kakizaki rat, a spontaneous nonobese model of type 2 diabetes. Biochim Biophys Acta. doi:10.1016/j.bbadis.2011.03.011 PubMedGoogle Scholar
  104. 104.
    Sena CM, Louro T, Matafome P, Nunes E, Monteiro P, Seiça R (2009) Antioxidant and vascular effects of gliclazide in type 2 diabetic rats fed high-fat diet. Physiol Res 58:203–209PubMedGoogle Scholar
  105. 105.
    Zhong MF, Shen WL, Tabuchi M, Nakamura K, Chen YC, Qiao CZ, He J, Yang J et al (2012) Differential changes of aorta and carotid vasodilation in type 2 diabetic GK and OLETF rats: paradoxical roles of hyperglycemia and insulin. Exp Diabetes Res. doi:10.1155/2012/429020 Google Scholar
  106. 106.
    Schrijvers BF, De Vriese AS, Van de Voorde J, Rasch R, Lameire NH, Flyvbjerg A (2004) Long-term renal changes in the Goto-Kakizaki rat, a model of lean type 2 diabetes. Nephrol Dial Transplant. doi:10.1093/ndt/gfh107 PubMedGoogle Scholar
  107. 107.
    Murakawa Y, Zhang W, Pierson CR, Brismar T, Ostenson CG, Efendic S, Sima AA (2002) Impaired glucose tolerance and insulinopenia in the GK-rat causes peripheral neuropathy. Diabetes Metab Res Rev. doi:10.1002/dmrr.326 PubMedGoogle Scholar
  108. 108.
    Guest PC, Abdel-Halim SM, Gross DJ, Clark A, Poitout V, Amaria R, Ostenson CG, Hutton JC (2002) Proinsulin processing in the diabetic Goto-Kakizaki rat. J Endocrinol. doi:10.1677/joe.0.1750637 PubMedGoogle Scholar
  109. 109.
    Amiri L, John A, Shafarin J, Adeghate E, Jayaprakash P, Yasin J, Howarth FC, Raza H (2015) Enhanced glucose tolerance and pancreatic Beta cell function by low dose aspirin in hyperglycemic insulin-resistant type 2 diabetic Goto-Kakizaki (GK) rats. Cell Physiol Biochem. doi:10.1159/000430162 PubMedGoogle Scholar
  110. 110.
    Koyama M, Wada R, Sakuraba H, Mizukami H, Yagihashi S (1998) Accelerated loss of islet beta cells in sucrose-fed Goto-Kakizaki rats, a genetic model of non-insulin-dependent diabetes mellitus. Am J Pathol. doi:10.1016/S0002-9440(10)65596-4 Google Scholar
  111. 111.
    Ostenson CG, Chen J, Sheu L, Gaisano HY (2007) Effects of palmitate on insulin secretion and exocytotic proteins in islets of diabetic Goto-Kakizaki rats. Pancreas. doi:10.1097/MPA.0b013e3180304825 PubMedGoogle Scholar
  112. 112.
    Maffucci JA, Gore AC (2006) Age-related changes in hormones and their receptors in animal models of female reproductive senescence. In: Conn M (ed) Handbook of models for human aging. Elsevier, Amsterdam, pp. 533–552CrossRefGoogle Scholar
  113. 113.
    Rubin BS (2000) Hypothalamic alterations and reproductive aging in female rats: evidence of altered luteinizing hormone-releasing hormone neuronal function. Biol Reprod. doi:10.1095/​biolreprod63.4.968 PubMedGoogle Scholar
  114. 114.
    Brinton RD (2008) The healthy cell bias of estrogen action: mitochondrial bioenergetics and neurological implications. Trends Neurosci. doi:10.1016/j.tins.2008.07.003 PubMedGoogle Scholar
  115. 115.
    Balthazart J, Ball GF (2006) Is brain estradiol a hormone or a neurotransmitter? Trends Neurosci. doi:10.1016/j.tins.2006.03.004 PubMedGoogle Scholar
  116. 116.
    Garcia-Ovejero D, Azcoitia I, Doncarlos LL, Melcangi RC, Garcia-Segura LM (2005) Glia-neuron crosstalk in the neuroprotective mechanisms of sex steroid hormones. Brain Res Brain Res Rev. doi:10.1016/j.brainresrev.2004.12.018 Google Scholar
  117. 117.
    Rune GM, Frotscher M (2005) Neurosteroid synthesis in the hippocampus: role in synaptic plasticity. Neuroscience. doi:10.1016/j.neuroscience.2005.03.056 Google Scholar
  118. 118.
    Prange-Kiel J, Wehrenberg U, Jarry H, Rune GM (2003) Para/autocrine regulation of estrogen receptors in hippocampal neurons. Hippocampus. doi:10.1002/hipo.10075 PubMedGoogle Scholar
  119. 119.
    Kolovou GD, Bilianou HG (2008) Influence of aging and menopause on lipids and lipoproteins in women. Angiology. doi:10.1177/0003319708319645 PubMedGoogle Scholar
  120. 120.
    Brinton RD (2013) Neurosteroids as regenerative agents in the brain: therapeutic implications. Nat Rev Endocrinol. doi:10.1038/nrendo.2013.31 PubMedGoogle Scholar
  121. 121.
    Acharya NK, Levin EC, Clifford PM, Han M, Tourtellotte R, Chamberlain D, Pollaro M, Coretti NJ et al (2013) Diabetes and hypercholesterolemia increase blood-brain barrier permeability and brain amyloid deposition: beneficial effects of the LpPLA2 inhibitor darapladib. J Alzheimers Dis. doi:10.3233/JAD-122254 PubMedGoogle Scholar
  122. 122.
    Jung JI, Ladd TB, Kukar T, Price AR, Moore BD, Koo EH, Golde TE, Felsenstein KM (2013) Steroids as γ-secretase modulators. FASEB J. doi:10.1096/fj.12-225649 Google Scholar
  123. 123.
    Sano M, Bell KL, Galasko D, Galvin JE, Thomas RG, van Dyck CH, Aisen PS (2011) A randomized, double-blind, placebo-controlled trial of simvastatin to treat Alzheimer disease. Neurology. doi:10.1212/WNL.0b013e318228bf11 Google Scholar
  124. 124.
    Feldman HH, Doody RS, Kivipelto M, Sparks DL, Waters DD, Jones RW, Schwam E, Schindler R et al (2010) Randomized controlled trial of atorvastatin in mild to moderate Alzheimer disease: LEADe. Neurology. doi:10.1212/WNL.0b013e3181d6476a Google Scholar
  125. 125.
    McGuinness B, Craig D, Bullock R, Passmore P (2016) Statins for the prevention of dementia. Cochrane Database Syst Rev. doi:10.1002/14651858.CD003160.pub3 Google Scholar
  126. 126.
    Stefani M, Liguri G (2009) Cholesterol in Alzheimer’s disease: unresolved questions. Curr Alzheimer Res. doi:10.2174/156720509787313899 PubMedGoogle Scholar
  127. 127.
    Whitmer RA, Sidney S, Selby J, Johnston SC, Yaffe K (2005) Midlife cardiovascular risk facts and risk of dementia in late life. Neurology 64:277–281PubMedCrossRefGoogle Scholar
  128. 128.
    Mielke MM, Zandi PP, Shao H, Waern M, Östling S, Guo X, Björkelund C, Lissner L et al (2010) The 32-year relationship between cholesterol and dementia from midlife to late life. Neurology. doi:10.1212/WNL.0b013e3181feb2bf PubMedPubMedCentralGoogle Scholar
  129. 129.
    Mielke MM, Zandi PP, Sjögren M, Gustafson D, Ostling S, Steen B, Skoog I (2005) High total cholesterol levels in late life associated with a reduced risk of dementia. Neurology 64:1689–1695PubMedCrossRefGoogle Scholar
  130. 130.
    Hannaoui S, Shim SY, Cheng YC, Corda E, Gilch S (2014) Cholesterol balance in prion diseases and Alzheimer’s disease. Viruses. doi:10.3390/v6114505 PubMedPubMedCentralGoogle Scholar
  131. 131.
    Vaya J, Schipper HM (2007) Oxysterols, cholesterol homeostasis, and Alzheimer disease. J Neurochem. doi:10.1111/j.1471-4159.2007.04689.x PubMedGoogle Scholar
  132. 132.
    Waters EM, Yildirim M, Janssen WG, Lou WY, McEwen BS, Morrison JH, Milner TA (2011) Estrogen and aging affect the synaptic distribution of estrogen receptor beta-immunoreactivity in the CA1 region of female rat hippocampus. Brain Res. doi:10.1016/j.brainres.2010.09.069 PubMedCentralGoogle Scholar
  133. 133.
    Ryan J, Carrière I, Carcaillon L, Dartigues JF, Auriacombe S, Rouaud O, Berr C, Ritchie K et al (2014) Estrogen receptor polymorphisms and incident dementia: the prospective 3C study. Alzheimers Dement. doi:10.1016/j.jalz.2012.12.008 Google Scholar
  134. 134.
    Foster TC (2012) Role of estrogen receptor alpha and beta expression and signaling on cognitive function during aging. Hippocampus. doi:10.1002/hipo.20935 PubMedGoogle Scholar
  135. 135.
    Ishunina TA, Swaab DF (2012) Decreased alternative splicing of estrogen receptor-alpha mRNA in the Alzheimer’s disease brain. Neurobiol Aging. doi:10.1016/j.neurobiolaging.2010.03.010 PubMedGoogle Scholar
  136. 136.
    Ishunina TA, Fischer DF, Swaab DF (2007) Estrogen receptor alpha and its splice variants in the hippocampus in aging and Alzheimer’s disease. Neurobiol Aging. doi:10.1016/j.neurobiolaging.2006.07.024 Google Scholar
  137. 137.
    Heldring N, Pike A, Andersson S, Matthews J, Cheng G, Hartman J, Tujague M, Ström A et al (2007) Estrogen receptors: how do they signal and what are their targets. Physiol Rev. doi:10.1152/physrev.00026.2006 PubMedGoogle Scholar
  138. 138.
    Weiser MJ, Foradori CD, Handa RJ (2008) Estrogen receptor beta in the brain: from form to function. Brain Res Rev. doi:10.1016/j.brainresrev.2007.05.013 PubMedGoogle Scholar
  139. 139.
    Zhao C, Matthews J, Tujague M, Wan J, Ström A, Toresson G, Lam EW, Cheng G et al (2007) Estrogen receptor beta2 negatively regulates the transactivation of estrogen receptor alfa in human breast cancer cells. Cancer Res. doi:10.1158/0008-5472.CAN-06-3505 Google Scholar
  140. 140.
    Lu B, Leygue E, Dotzlaw H, Murphy LJ, Murphy LC, Watson PH (1998) Estrogen receptor-beta mRNA variants in human and murine tissues. Mol Cell Endocrinol. doi:10.1016/S0303-7207(98)00050-1 Google Scholar
  141. 141.
    Chu S, Fuller PJ (1997) Identification of a splice variant of the rat estrogen receptor beta gene. Mol Cell Endocrinol. doi:10.1016/S0303-7207(97)00133-0 PubMedGoogle Scholar
  142. 142.
    Mao Z, Zhao L, Yao J, Ding F, Cadenas E, Brinton RD (2012) Sex-dependent bioenergetic and metabolic gene expression in the hippocampus: female brain ages differently from male brain. Paper presented at Society for Neuroscience. New Orleans, Los AngelesGoogle Scholar
  143. 143.
    Zhao WQ, De Felice FG, Fernandez S, Chen H, Lambert MP, Quon MJ, Krafft GA, Klein WL (2008) Amyloid beta oligomers induce impairment of neuronal insulin receptors. FASEB J. doi:10.1096/fj.06-7703com Google Scholar
  144. 144.
    Carro E, Trejo JL, Gomez-Isla T, LeRoith D, Torres-Aleman I (2002) Serum insulin-like growth factor I regulates brain amyloid-beta levels. Nat Med. doi:10.1038/nm1202-793 PubMedGoogle Scholar
  145. 145.
    Gao J, He J, Shi X, Stefanovic-Racic M, Xu M, O’Doherty RM, Garcia-Ocana A, Xie W (2012) Sex-specific effect of estrogen sulfotransferase on mouse models of type 2 diabetes. Diabetes. doi:10.2337/db11-1152 Google Scholar
  146. 146.
    Leiter EH, Chapman HD (1994) Obesity-induced diabetes (diabesity) in C57BL/KsJ mice produces aberrant trans-regulation of sex steroid sulfotransferase genes. J Clin Invest. doi:10.1172/JCI117194 Google Scholar
  147. 147.
    Clodfelder-Miller B, De Sarno P, Zmijewska AA, Song L, Jope RS (2005) Physiological and pathological changes in glucose regulate brain Akt and glycogen synthase kinase-3. J Biol Chem. doi:10.1074/jbc.M508824200 PubMedPubMedCentralGoogle Scholar
  148. 148.
    Clodfelder-Miller BJ, Zmijewska AA, Johnson GV, Jope RS (2006) Tau is hyperphosphorylated at multiple sites in mouse brain in vivo after streptozotocin-induced insulin deficiency. Diabetes. doi:10.2337/db06-0485 PubMedPubMedCentralGoogle Scholar
  149. 149.
    Borras C, Gambini J, Vina J (2007) Mitochondrial oxidant generation is involved in determining why females live longer than males. Front Biosci 12:1008–1013PubMedCrossRefGoogle Scholar
  150. 150.
    Viña J, Sastre J, Pallardó FV, Gambini J, Borrás C (2006) Role of mitochondrial oxidative stress to explain the different longevity between genders: protective effect of estrogens. Free Radic Res. doi:10.1080/10715760600952851 Google Scholar
  151. 151.
    Viña J, Borrás C, Gambini J, Sastre J, Pallardó FV (2005) Why females live longer than males: control of longevity by sex hormones. Sci Aging Knowl Environ 2005:pe17CrossRefGoogle Scholar
  152. 152.
    Laughlin GA, Kritz-Silverstein D, Barrett-Connor E (2010) Higher endogenous estrogens predict four year decline in verbal fluency in postmenopausal women: the rancho Bernardo study. Clin Endocrinol. doi:10.1111/j.1365-2265.2009.03599.x Google Scholar
  153. 153.
    Heys M, Jiang C, Cheng KK, Zhang W, Au Yeung SL, Lam TH, Leung GM, Schooling CM (2011) Lifelong endogenous estrogen exposure and later adulthood cognitive function in a population of naturally postmenopausal women from southern China: the Guangzhou biobank cohort study. Psychoneuroendocrinology. doi:10.1016/j.psyneuen.2010.11.009 PubMedGoogle Scholar
  154. 154.
    Colucci M, Cammarata S, Assini A, Croce R, Clerici F, Novello C, Mazzella L, Dagnino N et al (2006) The number of pregnancies is a risk factor for Alzheimer’s disease. Eur J Neurol. doi:10.1111/j.1468-1331.2006.01520.x PubMedGoogle Scholar
  155. 155.
    Sobow T, Kloszewska I (2004) Parity, number of pregnancies, and the age of onset of Alzheimer’s disease. J Neuropsychiatry Clin Neurosci. doi:10.1176/jnp.16.1.120-a PubMedGoogle Scholar
  156. 156.
    Ptok U, Barkow K, Heun R (2002) Fertility and number of children in patients with Alzheimer’s disease. Arch Womens Ment Health. doi:10.1007/s00737-002-0142-6 PubMedGoogle Scholar
  157. 157.
    Christensen H, Leach LS, Mackinnon A (2010) Cognition in pregnancy and motherhood: prospective cohort study. Br J Psychiatry. doi:10.1192/bjp.bp.109.068635 Google Scholar
  158. 158.
    Barha CK, Lieblich SE, Chow C, Galea LA (2015) Multiparity-induced enhancement of hippocampal neurogenesis and spatial memory depends on ovarian hormone status in middle age. Neurobiol Aging. doi:10.1016/j.neurobiolaging.2015.04.007 PubMedGoogle Scholar
  159. 159.
    Mielke MM, Vemuri P, Rocca WA (2014) Clinical epidemiology of Alzheimer’s disease: assessing sex and gender differences. Clin Epidemiol. doi:10.2147/CLEP.S37929 PubMedPubMedCentralGoogle Scholar
  160. 160.
    Vagelatos NT, Eslick GD (2013) Type 2 diabetes as a risk factor for Alzheimer’s disease: the confounders, interactions, and neuropathology associated with this relationship. Epidemiol Rev. doi:10.1093/epirev/mxs012 PubMedGoogle Scholar
  161. 161.
    Sanz CM, Hanaire H, Vellas BJ, Sinclair AJ, Andrieu S, REAL.FR Study Group (2012) Diabetes mellitus as a modulator of functional impairment and decline in Alzheimer’s disease. The Real FR cohort Diabet Med. doi:10.1111/j.1464-5491.2011.03445.x PubMedGoogle Scholar
  162. 162.
    Williams JW, Plassman BL, Burke J, Benjamin S (2010) Preventing Alzheimer’s disease and cognitive decline. Evid Rep Technol Assess (Full Rep) (193):1–727Google Scholar

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • E. Candeias
    • 1
    • 2
  • A. I. Duarte
    • 1
    • 2
  • I. Sebastião
    • 1
  • M. A. Fernandes
    • 3
    • 4
  • A. I. Plácido
    • 1
    • 5
  • C. Carvalho
    • 1
    • 2
  • S. Correia
    • 1
    • 2
  • R. X. Santos
    • 1
    • 3
  • R. Seiça
    • 6
  • M. S. Santos
    • 1
    • 4
  • C. R. Oliveira
    • 1
    • 7
  • P. I. Moreira
    • 1
    • 6
  1. 1.CNC- Center for Neuroscience and Cell Biology, Rua Larga, Faculty of Medicine (Pólo 1, 1st Floor)University of CoimbraCoimbraPortugal
  2. 2.Institute for Interdisciplinary Research (IIIUC)University of CoimbraCoimbraPortugal
  3. 3.Life Sciences DepartmentUniversity of CoimbraCoimbraPortugal
  4. 4.Instituto do Mar, Life Sciences DepartmentUniversity of CoimbraCoimbraPortugal
  5. 5.Faculty of MedicineUniversity of CoimbraCoimbraPortugal
  6. 6.Institute of Physiology, Faculty of MedicineUniversity of CoimbraCoimbraPortugal
  7. 7.Institute of Biochemistry, Faculty of MedicineUniversity of CoimbraCoimbraPortugal

Personalised recommendations