Focus on the Correlations between Alzheimer’s Disease and Type 2 Diabetes

Author(s): Vincenzo Fiore* , Antonia De Rosa , Paolo Falasca , Massimo Marci , Edoardo Guastamacchia , Brunella Licchelli , Vito Angelo Giagulli , Giovanni De Pergola , Antonella Poggi , Vincenzo Triggiani* .

Journal Name: Endocrine, Metabolic & Immune Disorders - Drug Targets

Volume 19 , Issue 5 , 2019

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Graphical Abstract:


Background: In the last decades, both diabetes mellitus and Alzheimer's disease are constantly increasing. Affected individuals, therefore, represent an enormous problem for the society, governments and global organizations. These diseases are usually considered as independent conditions, but increasing evidence shows that there are links between these two disorders.

Methods: In this review, we analyzed common features present in Alzheimer’s disease and diabetes mellitus, showing how these two diseases are strictly correlated to each other.

Results: Some pathogenetic factors are shared by Type 2 Diabetes and Alzheimer’s Disease: chronic inflammation, oxidative stress, mitochondrial dysfunction, adiponectin deficiency, different expression of plasma cholinesterase activity and vascular damage could represent a possible explanation for the coexistence of these two conditions in many patients.

Conclusion: A better understanding of this issue and an appropriate management of diabetes by means of physical activity, low fat diet, and drugs to achieve a good glycemic control, avoiding both hyperglycemia and hypoglycemia, can represent a way to prevent cognitive decline and Alzheimer’s disease.

Keywords: Alzheimer's disease, Hyperglycemia, Insulin resistance, Type 2 diabetes mellitus, chronic inflammation, neurodegenerative disorder.

Mayer, F.; Di Pucchio, A.; Lacorte, E.; Bacigalupo, I.; Marzolini, F.; Ferrante, G.; Minardi, V.; Masocco, M.; Canevelli, M.; Di Fiandra, T.; Vanacore, N. Alzheimer disease and vascular dementia due to modifiable risk factors: The impact of primary prevention in Europe and in Italy. Dement. Geriatr. Cogn. Disord. Extra, 2018, 8, 60-71.
Selkoe, D.J. The molecular pathology of Alzheimer’s disease. Neuron, 1991, 6, 487-498.
Mattson, M.P. Pathway towards and away from Alzheimer’s disease. Nature, 2004, 430, 631-639.
Armstrong, R.A. The molecular biology of senile plaques and neurofibrillary tangles in Alzheimer’s disease. Folia Neuropathol., 2009, 47, 289-299.
Hardy, J.; Selkoe, D.J. The amyloid hypothesis of Alzheimer’s disease: Progress and problems on the road to therapeutics. Science, 2002, 297, 353-356.
Cross, D.; Vial, C.; Maccioni, R.B. A tau-like protein interacts with stress fibers and microtubules in human and rodent cultured cell lines. J. Cell Sci., 1993, 105, 51-60.
Kosik, K.S.; Joachim, C.L.; Selkoe, D.J. Microtubule-associated protein tau is a major antigenic component of paired helical filaments in Alzheimer disease. PNAS, 1986, 83, 4044-4048.
Maccioni, R.B.; Cambiazo, V. Role of microtubule-associated proteins in the control of microtubule assembly. Physiol. Rev., 1995, 75, 835-864.
Mandelkow, E.M.; Biernat, J.; Drewes, G.; Gustke, N.; Trinczek, B.; Mandelkow, E. Tau domains, phosphorylation, and interactions with microtubules. Neurobiol. Aging, 1995, 16, 355-363.
Lista, S.; O’Bryant, S.E.; Blennow, K.; Dubois, B.; Hugon, J.; Zetterberg, H.; Hampel, H. Biomarkers in sporadic and familial Alzheimer’s disease. J. Alzheimers Dis., 2015, 47(2), 291-317.
Holtzman, D.M.; Morris, J.C.; Goate, A.M. Alzheimer’s disease: The challenge of the second century. Sci. Transl. Med., 2011, 3, 77sr1.
Brands, A.M.; Van den Berg, E.; Manschot, S.M.; Biessels, G.J.; Kappelle, L.J.; De Haan, E.H.; Kessels, R.P. A detailed profile of cognitive dysfunction and its relation to psychological distress in patients with type 2 diabetes mellitus. J. Int. Neuropsychol. Soc., 2007, 13, 288-297.
Awad, N.; Gagnon, M.; Messier, C. The relationship between impaired glucose tolerance, type 2 diabetes, and cognitive function. J. Clin. Exp. Neuropsychol., 2004, 26, 1044-1080.
Morris, M.C.; Evans, D.A.; Bienias, J.L.; Tangney, C.C.; Wilson, R.S. Dietary fat intake and 6-year cognitive change in an older biracial community population. Neurology, 2004, 62, 1573-1579.
Ortega, R.M.; Requejo, A.M.; Andres, P.; Lopez-Sobaler, A.M.; Quintas, M.E.; Redondo, M.R.; Navia, B.; Rivas, T. Dietary intake and cognitive function in a group of elderly people. Am. J. Clin. Nutr., 1997, 66, 803-809.
Prickett, C.; Brennan, L.; Stolwyk, R. Examining the relationship between obesity and cognitive function: A systematic literature review. Obes. Res. Clin. Pract., 2015, 9, 93-113.
Wong, R.H.; Scholey, A.; Howe, P.R. Assessing premorbid cognitive ability in adults with type 2 diabetes mellitus-A review with implications for future intervention studies. Curr. Diabetes. Rep., 2014, 14, 547.
Winocur, G.; Greenwood, C.E. Studies of the effects of high fat diets on cognitive function in a rat model. Neurobiol. Aging, 2005, 26(Suppl. 1), 46-49.
Beydoun, M.A.; Beydoun, H.A.; Wang, Y. Obesity and central obesity as risk factors for incident dementia and its subtypes: A systematic review and meta-analysis. Obes. Rev., 2008, 9, 204-218.
Kalmijn, S.; Launer, L.J.; Ott, A.; Witteman, J.C.; Hofman, A.; Breteler, M.M. Dietary fat intake and the risk of incident dementia in the Rotterdam study. Ann. Neurol., 1997, 42, 776-782.
Kivipelto, M.; Ngandu, T.; Fratiglioni, L.; Viitanen, M.; Kareholt, I.; Winblad, B.; Helkala, E.L.; Tuomilehto, J.; Soininen, H.; Nissinen, A. Obesity and vascular risk factors at midlife and the risk of dementia and Alzheimer disease. Arch. Neurol., 2005, 62, 1556-1560.
Luchsinger, J.A.; Tang, M.X.; Shea, S.; Mayeux, R. Caloric intake and the risk of Alzheimer disease. Arch. Neurol., 2002, 59, 1258-1263.
De Felice, F.G.; Lourenco, M.V. Brain metabolic stress and neuroinflammation at the basis of cognitive impairment in Alzheimer’s disease. Front. Aging Neurosci., 2015, 7, 94.
Vagelatos, N.T.; Eslick, G.D. Type 2 diabetes as a risk factor for Alzheimer’s disease: The confounders, interactions, and neuropathology associated with this relationship. Epidemiol. Rev., 2013, 35, 152-160.
Sims-Robinson, C.; Kim, B.; Rosko, A.; Feldman, E.L. How does diabetes accelerate Alzheimer disease pathology? Nat. Rev. Neurol., 2010, 6(10), 551-559.
Dimitriadis, G.; Mitrou, P.; Lambadiari, V.; Maratou, E.; Raptis, S.A. Insulin effects in muscle and adipose tissue. Diabetes Res. Clin. Pract., 2011, 93, S52-S59.
Lacroix, M.C.; Badonnel, K.; Meunier, N.; Tan, F.; Schlegel-Le Poupon, C.; Durieux, D.; Monnerie, R.; Baly, C.; Congar, P.; Salesse, R.; Caillol, M. Expression of insulin system in the olfactory epithelium: First approaches to its role and regulation. J. Neuroendocrinol., 2008, 20, 1176-1190.
Kuwabara, T.; Kagalwala, M.N.; Onuma, Y.; Ito, Y.; Warashina, M.; Terashima, K.; Sanosaka, T.; Nakashima, K.; Gage, F.H.; Asashima, M. Insulin biosynthesis in neuronal progenitors derived from adult hippocampus and the olfactory bulb. EMBO Mol. Med., 2011, 3, 742-754.
Bingham, E.M.; Hopkins, D.; Smith, D.; Pernet, A.; Hallett, W.; Reed, L.; Marsden, P.K.; Amiel, S.A. The role of insulin in human brain glucose metabolism: An 18 fluoro-deoxyglucose positron emission tomography study. Diabetes, 2002, 51, 3384-3390.
Zhao, W.Q.; Chen, H.; Quon, M.J.; Alkon, D.L. Insulin and the insulin receptor in experimental models of learning and memory. Eur. J. Pharmacol., 2004, 490, 71-81.
Huang, T.J.; Verkhratsky, A.; Fernyhough, P. Insulin enhances mitochondrial inner membrane potential and increases ATP levels through phosphoinositide 3-kinase in adult sensory neurons. Mol. Cell. Neurosci., 2005, 28, 42-54.
Duarte, A.I.; Proença, T.; Oliveira, C.R.; Santos, M.S.; Rego, A.C. Insulin restores metabolic function in cultured cortical neurons subjected to oxidative stress. Diabetes, 2006, 55, 2863-2870.
Stanley, M.; Macauley, S.L.; Holtzman, D.M. Changes in insulin and insulin signaling in Alzheimer’s disease: Cause or consequence? J. Exp. Med., 2016, 213(8), 1375-1385.
Salkovic-Petrisic, M.; Tribl, F.; Schmidt, M.; Hoyer, S.; Riederer, P. Alzheimer-like changes in protein kinase B and glycogen synthase kinase-3 in rat frontal cortex and hippocampus after damage to the insulin signaling pathway. J. Neurochem., 2006, 96, 1005-1015.
Baker, L.D.; Cross, D.J.; Minoshima, S.; Belongia, D.; Watson, G.S.; Craft, S. Insulin resistance and Alzheimer-like reductions in regional cerebral glucose metabolism for cognitively normal adults with prediabetes or early type 2 diabetes. Arch. Neurol., 2010, 68, 51-57.
Nobuyuki, Kimura. Diabetes Mellitus Induces Alzheimer’s Disease Pathology: Histopathological Evidence from Animal Models. Int. J. Mol. Sci., 2016, 17, 503.
Ho, L.; Qin, W.; Pompl, P.N.; Xiang, Z.; Wang, J.; Zhao, Z.; Peng, Y.; Cambareri, G.; Rocher, A.; Mobbs, C.V. et al. Diet-induced insulin resistance promotes amyloidosis in a transgenic mouse model of Alzheimer’s disease. FASEB J., 2004, 18, 902-904.
Li, Y.; Duffy, K.B.; Ottinger, M.A.; Ray, B.; Bailey, J.A.; Holloway, H.W.; Tweedie, D.; Perry, T.; Mattson, M.P.; Kapogiannis, D. et al. GLP-1 receptor stimulation reduces amyloid- peptide accumulation and cytotoxicityin cellular and animal models of Alzheimer’s disease. J. Alzheimers Dis., 2010, 19, 1205-1219.
Plaschke, K.; Kopitz, J.; Siegelin, M.; Schliebs, R.; Salkovic-Petrisic, M.; Riederer, P.; Hoyer, S. Insulin-resistant brain state after intracerebroventricular streptozotocin injection exacerbates Alzheimer-like changes inTg2576 APP-overexpressing mice. J. Alzheimers Dis., 2010, 19, 691-704.
Takeda, S.; Sato, N.; Uchio-Yamada, K.; Sawada, K.; Kunieda, T.; Takeuchi, D.; Kurinami, H.; Shinohara, M.; Rakugi, H.; Morishita, R. Diabetes-accelerated memory dysfunction via cerebrovascular inflammationand a deposition in an Alzheimer mouse model with diabetes. PNAS, 2010, 107, 7036-7041.
Bitela, C.L.; Kasinathanb, C.; Kaswalab, R.H.; Klein, W.L.; Frederiksea, P.H. Amyloid- and tau pathology of Alzheimer’s disease induced by diabetes in a rabbit animal model. J. Alzheimers Dis., 2012, 32, 291-305.
Currais, A.; Prior, M.; Lo, D.; Jolivalt, C.; Schubert, D.; Maher, P. Diabetes exacerbates amyloid andneurovascular pathology in aging-accelerated mice. Aging Cell, 2012, 11, 1017-1026.
Maesako, M.; Uemura, K.; Kubota, M.; Kuzuya, A.; Sasaki, K.; Asada, M.; Watanabe, K.; Hayashida, N.; Ihara, M.; Ito, H.; Shimohama, S.; Kihara, T.; Kinoshita, A. Environmental enrichment ameliorated high-fat diet-induced a deposition andmemory deficit in APP transgenic mice. Neurobiol. Aging, 2012, 33, 1011.e11-23..
Son, S.M.; Song, H.; Byun, J.; Park, K.S.; Jang, H.C.; Park, Y.J.; Mook-Jung, I. Accumulation of autophagosomes contributes to enhanced amyloidogenic APP processing under insulin-resistant conditions. Autophagy, 2012, 8, 1842-1844.
Yamamoto, N.; Matsubara, T.; Sobue, K.; Tanida, M.; Kasahara, R.; Naruse, K.; Taniura, H.; Sato, T.; Suzuki, K. Brain insulin resistance accelerates a fibrillogenesis by inducing GM1 ganglioside clustering in the presynaptic membranes. J. Neurochem., 2012, 121, 619-628.
Chen, Y.; Liang, Z.; Blanchard, J.; Dai, C.L.; Sun, S.; Lee, M.H.; Grundke-Iqbal, I.; Iqbal, K.; Liu, F.; Gong, C.X. A non-transgenic mouse model (icv-STZ mouse) of Alzheimer’s disease: Similarities to and differences from the transgenic model (3xTg-AD mouse). Mol. Neurobiol., 2013, 47, 711-725.
Yang, Y.; Wu, Y.; Zhang, S.; Song, W. High glucose promotes A production by inhibiting APP degradation. PLoS ONE, 2013, 8e69824
46. Mehlaa, J.; Chauhanc, B.C.; Chauhana, N.B. Experimental induction of type 2 diabetes in aging-accelerated mice triggered alzheimer-like pathology and memory deficits. J. Alzheimers Dis., 2014, 39, 145-162.
Biessels, G.J.; Y.D, Reijmer. Brain changes underlying cognitive dysfunction in diabetes: What can we learn from MRI? Diabetes, 2014, 63, 2244-2252.
Medhi, B.; Chakrabarty, M. Insulin resistance: An emerging link in Alzheimer’s disease. Neurol. Sci., 2013, 34, 1719-1725.
Unger, J.W.; Livingston, J.N.; Moss, A.M. Insulin receptors in the central nervous system: Localization, signaling mechanism and functional aspects. Prog. Neurobiol., 1991, 36, 343-362.
Gray, S.M.; Meijer, R.I.; Barrett, E.J. Insulin regulates brain function, but how does it get there? Diabetes, 2014, 63, 3992-3997.
De la Monte, S.M.; Chen, G.J.; Rivera, E.; Wands, J.R. Neuronal thread protein regulation and interaction with microtubule-associated proteins in SH-Sy5y neuronal cells. Cell. Mol. Life Sci., 2003, 60, 2679-2691.
Park, C.R. Cognitive effects of insulin in the central nervous system. Neurosci. Biobehav. Rev., 2001, 25, 311-323.
Zhao, W.Q.; Alkon, D.L. Role of insulin and insulin receptor in learning and memory. Mol. Cell. Endocrinol., 2001, 177, 125-134.
Plum, L.; Schubert, M.; Brüning, J.C. The role of insulin receptor signaling in the brain. Trends Endocrinol. Metab., 2005, 16, 59-65.
Kleinridders, A.; Ferris, H.A.; Cai, W.; Kahn, C.R. Insulin action in brain regulates systemic metabolism and brain function. Diabetes, 2014, 63, 2232-2243.
McNay, E.C. Insulin and ghrelin: Peripheral hormones modulating memory and hippocampal function. Curr. Opin. Pharmacol., 2007, 7, 628-632.
Sridhar, G.R.; Lakshmi, G.; Nagamani, G. Emerging links between type 2 diabetes and Alzheimer’s disease. World J. Diabetes, 2015, 6(5), 744-751.
Lannert, H.; Hoyer, S. Intracerebroventricular administration of streptozotocin causes long-term diminutions in learning and memory abilities and in cerebral energy metabolism in adult rats. Behav. Neurosci., 1998, 112, 1199-1208.
Arrieta-Cruz, I.; Gutiérrez-Juárez, R. The role of insulin resistance and glucose metabolism dysregulation in the development of Akzheimer’s disease. Rev. Invest. Clin., 2016, 68, 53-58.
Matsuzaki, T.; Sasaki, K.; Tanizaki, Y.; Hata, J.; Fujimi, K.; Matsui, Y.; Sekita, A.; Suzuki, S.O.; Kanba, S.; Kiyohara, Y.; Iwaki, T. Insulin resistance is associated with the pathology of Alzheimer disease: The Hisayama study. Neurology, 2010, 75, 764-770.
Frolich, L.; Blum-Degen, D.; Bernstein, H.G.; Engelsberger, S.; Humrich, J.; Laufer, S.; Muschner, D.; Thalheimer, A.; Türk, A.; Hoyer, S.; Zöchling, R.; Boissl, K.W.; Jellinger, K.; Riederer, P. Brain insulin and insulin receptors in aging and sporadic Alzheimer’s disease. J. Neural Transm. (Vienna), 1998, 105, 423-438.
Gasparini, L.; Gouras, G.K.; Wang, R.; Gross, R.S.; Beal, M.F.; Greengard, P.; Xu, H. Stimulation of beta-amyloid precursor protein trafficking by insulin reduces intraneronal beta-amyloid and requires mitogen-activated protein kinase signaling. J. Neurosci., 2001, 21, 2561-2570.
Tang, W.J. Targeting insulin-degrading enzyme to treat type 2 diabetes. Trends Endocrinol. Metab., 2016, 27(1), 24-34.
Shiiki, T.; Ohtsuki, S.; Kurihara, A.; Naganuma, H.; Nishimura, K.; Tachikawa, M.; Hosoya, K.; Terasaki, T. Brain insulin impairs amyloid-beta (1-40) clearance from the brain. J. Neurosci., 2004, 24, 9632-9637.
Kang, S.; Lee, Y.H.; Lee, J.E. Metabolism-centric overview of the pathogenesis of Alzheimer’s disease. Yonsei Med. J., 2017, 58(3), 479-488.
Qiu, W.Q.; Folstein, M.F. Insulin, insulin-degrading enzyme and amyloid-beta peptide in Alzheimer’s disease: Review and hypothesis. Neurobiol. Aging, 2006, 27, 190-198.
Schubert, M.; Brazil, D.P.; Burks, D.J.; Kushner, J.A.; Ye, J.; Flint, C.L.; Farhang-Fallah, J.; Dikkes, P.; Warot, X.M.; Rio, C.; Corfas, G.; White, M.F. Insulin receptor substrate-2 deficiency impairs brain growth and promotes tau phosphorylation. J. Neurosci., 2003, 23(18), 7084-7092.
Schubert, M.; Gautam, D.; Surjo, D.; Ueki, K.; Baudler, S.; Schubert, D.; Kondo, T. Alber. J.; Galldiks, N.; Küstermann, E.; Arndt, S.; Jacobs, A.H.; Krone, W.; Kahn, C.R.; Brüning, J.C. Role for neuronal insulin resistance in neurodegenerative diseases. Proc. Natl. Acad. Sci. USA, 2004, 101(9), 3100-3105.
Farr, S.A.; Sandoval, K.E.; Niehoff, M.L.; Witt, K.A.; Kumar, V.B.; Morley, J.E. Peripheral administration of GSK-3β antisense oligonucleotide improves learning and memory in SAMP8 and Tg2576 mouse models of Alzheimer’s disease. J. Alzheimers Dis., 2016, 54, 1339-1348.
de la Monte, S.M. Contributions of brain insulin resistance and deficiency in amyloid-related neurodegeneration in Alzheimer’s disease. Drugs, 2012, 72(1), 49-66.
Messier, C.; Teutenberg, K. The role of insulin, insulin growth factor, and insulin-degrading enzyme in brain aging and Alzheimer’s disease. Neural Plast., 2005, 12(4), 311-328.
Craft, S. Insulin resistance syndrome and Alzheimer disease: Pathophysiologic mechanisms and therapeutic implications. Alzheimer Dis. Assoc. Disord., 2006, 20(4), 298-301.
Rivera, E.J.; Goldin, A.; Fulmer, N.; Tavares, R.; Wands, J.R.; de la Monte, S.M. Insulin and insulin-like growth factor expression and function deteriorate with progression of Alzheimer’s disease: Link to brain reductions in acetylcholine. J. Alzheimers Dis., 2005, 8(3), 247-268.
Xie, L.; Helmerhorst, E.; Taddei, K.; Plewright, B.; Van Bronswijk, W.; Martins, R. Alzheimer’s β-amyloid peptides compete for insulin binding to the insulin receptor. J. Neurosci., 2002, 22(10), RC221.
Steen, E.; Terry, B.M.; Rivera, E.J.; Cannon, J.L.; Neely, T.R.; Tavares, R.; Xu, X.J.; Wands, J.R.; de la Monte, S.M. Impaired insulin and insulin-like growth factor expression and signaling mechanisms in Alzheimer’s disease-is this type 3 diabetes? J. Alzheimers Dis., 2005, 7, 63-80.
Ribe, E.M.; Lovestone, S. Insulin signalling in Alzheimer’s disease and diabetes: From epidemiology to molecular links. J. Intern. Med., 2016, 280(5), 430-442.
Verdile, G.; Keane, K.N.; Cruzat, V.F.; Medic, S.; Sabale, M.; Rowles, J.; Wijesekara, N.; Martins, R.N.; Fraser, P.E.; Newsholme, P. Inflammation and oxidative stress: The molecular connectivity between insulin resistance, obesity, and Alzheimer’s disease. Mediators Inflamm., 2015, 2015105828
Walker, J.M.; Fiona, E. Harrison. Shared neuropathological characteristics of obesity, type 2 diabetes and Alzheimer’s disease: Impacts on cognitive decline. Nutrients, 2015, 7, 7332-7357.
Rosales-Corral, S.; Tan, D.X.; Manchester, L.; Reiter, R.J. Diabetes and Alzheimer disease, two overlapping pathologies with the same background: Oxidative stress. Oxid. Med. Cell. Longev., 2015, 2015985845
Ng, R.C.; Cheng, O.Y.; Jian, M.; Kwan, J.S.; Ho, P.W.; Cheng, K.K.; Yeung, P.K.; Zhou, L.L.; Hoo, R.L.; Chung, S.K.; Xu, A.; Lam, K.S.; Chan, K.H. Chronic adiponectin deficiency leads to Alzheimer’s disease-like cognitive impairments and pathologies through AMPK inactivation and cerebral insulin resistance in aged mice. Mol. Neurodegener., 2016, 11(1), 71.
Hosoi, M.; Hori, K.; Konishi, K.; Tani, M.; Tomioka, H.; Kitajima, Y.; Akashi, N.; Inamoto, A.; Minami, S.; Izuno, T.; Umezawa, K.; Horiuchi, K.; Hachisu, M. Plasma cholinesterase activity in Alzheimer’s disease. Neurodegener. Dis., 2015, 15(3), 188-190.
Cook, D.G.; Leverenz, J.B.; McMillan, P.J.; Kulstad, J.J.; Ericksen, S.; Roth, R.A.; Schellenberg, G.D.; Jin, L.W.; Kovacina, K.S.; Craft, S. Reduced hippocampal insulin-degrading enzyme in late-onset Alzheimer’s disease is associated with the apolipoprotein E-epsilon4 allele. Am. J. Pathol., 2003, 162, 313-319.
Caccamo, A.; Oddo, S.; Sugarman, M.C.; Akbari, Y.; LaFerla, F.M. Age- and region-dependent alterations in abeta-degrading enzymes: Implications for abeta-induced disorders. Neurobiol. Aging, 2005, 26, 645-654.
Czirr, E.; Wyss-Coray, T. The immunology of neurodegeneration. J. Clin. Invest., 2012, 122, 1156-1163.
Swardfager, W.; Lanctot, K.; Rothenburg, L.; Wong, A.; Cappell, J.; Herrmann, N. A meta-analysis of cytokines in Alzheimer’s disease. Biol. Psychiatry, 2010, 68, 930-941.
Hotamisligil, G.S. Inflammation and metabolic disorders. Nature, 2006, 444, 860-867.
Hotamisligil, G.S.; Shargill, N.S.; Spiegelman, B.M. Adipose expression of tumor necrosis factor-alpha: Direct role in obesity-linked insulin resistance. Science, 1993, 259, 87-91.
Hotamisligil, G.S.; Shargill, N.S.; Spiegelman, B.M. Adipose expression of tumor necrosis factor-alpha: Direct role in obesity-linked insulin resistance. Science, 1993, 259(5091), 87-91.
Cummings, J.L. Treatment of Alzheimer’s disease: Current and future therapeutic approaches. Rev. Neurol. Dis., 2004, 1, 60-69.
Heneka, M.T.; O’Banion, M.K. Inflammatory processes in Alzheimer’s disease. J. Neuroimmunol., 2007, 184, 69-91.
Pistell, P.J.; Morrison, C.D.; Gupta, S.; Knight, A.G.; Keller, J.N.; Ingram, D.K.; Bruce-Keller, A.J. Cognitive impairment following high fat diet consumption is associated with brain inflammation. J. Neuroimmunol., 2010, 219(1-2), 25-32.
Fishel, M.A.; Watson, G.S.; Montine, T.J.; Wang, Q.; Green, P.S.; Kulstad, J.J.; Cook, D.G.; Peskind, E.R.; Baker, L.D.; Goldgaber, D.; Nie, W.; Asthana, S.; Plymate, S.R.; Schwartz, M.W.; Craft, S. Hyperinsulinemia provokes synchronous increases in central inflammation and beta-amyloid in normal adults. Arch. Neurol., 2005, 62, 1539-1544.
Miklossy, J.; McGeer, P.L. Common mechanisms involved in Alzheimer’s disease and type 2 diabetes: A key role of chronic bacterial infection and inflammation. Aging (Albany NY), 2016, 8(4), 575-588.
Carvalho, C.; Cardoso, S.; Correia, S.C.; Santos, R.X.; Santos, M.S.; Baldeiras, I.; Oliveira, C.R.; Moreira, P.I. Metabolic alterations induced by sucrose intake and Alzheimer’s disease promote similar brain mitochondrial abnormalities. Diabetes, 2012, 61(5), 1234-1242.
Zamora, M.; Villena, J.A. Targeting mitochondrial biogenesis to treat insulin resistance. Curr. Pharm. Des., 2014, 20(35), 5527-5557.
Gerbitz, K.D.; Gempel, K.; Brdiczka, D. Mitochondria and diabetes. Genetic, biochemical, and clinical implications of the cellular energy circuit. Diabetes, 1996, 45, 113-126.
Moreira, P.I.; Santos, M.S.; Seica, R.; Oliveira, C.R. Brain mitochondrial dysfunction as a link between Alzheimer’s disease and diabetes. J. Neurol. Sci., 2007, 257, 206-214.
Orth, M.; Schapira, A.H. Mitochondria and degenerative disorders. Am. J. Med. Genet., 2001, 106, 27-36.
Calabrese, V.; Scapagnini, G.; Giuffrida Stella, A.M.; Bates, T.E.; Clark, J.B. Mitochondrial involvement in brain function and dysfunction: Relevance to aging, neurodegenerative disorders and longevity. Neurochem. Res., 2001, 26, 739-764.
Tateya, S.; Kim, F.; Tamori, Y. Recent advances in obesity-induced inflammation and insulin resistance. Front. Endocrinol. (Lausanne), 2013, 4, 93.
Iwasaki, T.; Yoneda, M.; Nakajima, A.; Terauchi, Y. Serum butyrylcholinesterase is strongly associated with adiposity, the serum lipid profile and insulin resistance. Intern. Med., 2007, 46, 1633-1639.
Kamal, M.A.; Tan, Y.; Seale, J.P.; Qu, X. Targeting BuChE-inflammatory pathway by SK0506 to manage type 2 diabetes and Alzheimer disease. Neurochem. Res., 2009, 34, 2163-2169.
Perry, E.K.; Tomlinson, B.E.; Blessed, G.; Bergmann, K.; Gibson, P.H.; Perry, R.H. Correlation of cholinergic abnormalities with senileplaques and mental test scores in senile dementia. Br. Med. J., 1978, 25, 1457-1459.
Darvesh, S.; Hopkins, D.A.; Geula, C. Neurobiology of butyrylcholinesterase. Nat. Rev. Neurosci., 2003, 4, 131-138.
Pavlov, V.A.; Ochani, M.; Gallowitsch-Puerta, M.; Ochani, K.; Huston, J.M.; Czura, C.J.; Al-Abed, Y.; Tracey, K.J. Central muscarinic cholinergic regulation of the systemic inflammatory response during endotoxemia. Proc. Natl. Acad. Sci. USA, 2006, 103, 5219-5223.
Mabley, J.G.; Pacher, P.; Szabo, C. Activation of the cholinergic anti-inflammatory pathway reduces ricin-induced mortality and organ failure in mice. Mol. Med., 2009, 15, 166-172.
Ascher-Svanum, H.; Chen, Y.F.; Hake, A.; Kahle-Wrobleski, K.; Schuster, D.; Kendall, D.; Heine, R.J. Cognitive and functional decline in patients with mild Alzheimer dementia with or without comorbid diabetes. Clin. Ther., 2015, 37(6), 1195-1205.
Li, J.; Cesari, M.; Liu, F.; Dong, B.; Vellas, B. Effects of diabetes mellitus on cognitive decline in patients with alzheimer disease: A systematic review. Can. J. Diabetes, 2017, 41(1), 114-119.
Lee, J.H.; Choi, Y.; Jun, C.; Hong, Y.S.; Cho, H.B.; Kim, J.E.; Lyoo, I.K. Neurocognitive changes and their neural correlates in patients with type 2 diabetes mellitus. Endocrinol. Metab. (Seoul), 2014, 29(2), 112-121.
Pistell, P.J.; Morrison, C.D.; Gupta, S.; Knight, A.G.; Keller, J.N.; Ingram, D.K.; Bruce-Keller, A.J. Cognitive impairment following high fat diet consumption is associated with brain inflammation. J. Neuroimmunol., 2010, 219, 25-32.
Rosi, S.; Pert, C.B.; Ruff, M.R.; McGann-Gramling, K.; Wenk, G.L. Chemokine receptor 5 antagonist D-Ala-peptide T-amide reduces microglia and astrocyte activation within the hippocampus in a neuroinflammatory rat model of Alzheimer’s disease. Neuroscience, 2005, 134, 671-676.
Crane, P.K.; Walker, R.; Hubbard, R.A.; Li, G.; Nathan, D.M.; Zheng, H.; Haneuse, S.; Craft, S.; Montine, T.J.; Kahn, S.E.; McCormick, W.; McCurry, S.M.; Bowen, J.D.; Larson, E.B. Glucose levels and risk of dementia. N. Engl. J. Med., 2013, 369, 540-548.
McCrimmon, R.J.; Ryan, C.M.; Frier, B.M. Diabetes and cognitivedysfunction. Lancet, 2012, 379, 2291-2299.
Whitmer, R.A. Type 2 diabetes and risk of cognitive impairment and dementia. Curr. Neurol. Neurosci. Rep., 2007, 7(5), 373-380.
Holscher, C. First clinical data of the neuroprotective effects of nasal insulin application in patients with Alzheimer’s disease. Alzheimers Dement., 2014, 10(Suppl. 1), S33-S37.
Coley, N.; Andrieu, S.; Gardette, V.; Gillette-Guyonnet, S.; Sanz, C.; Vellas, B.; Grand, A. Dementia prevention: Methodological explanations for inconsistent results. Epidemiol. Rev., 2008, 30, 35-66.
Arvanitakis, Z.; Schneider, J.A.; Wilson, R.S.; Bienias, J.L.; Kelly, J.F.; Evans, D.A.; Bennett, D.A. Statins, incident Alzheimer disease, change in cognitive function, and neuropathology. Neurology, 2008, 70(19 Pt2), 1795-1802.
Cramer, C.; Haan, M.N.; Galea, S.; Langa, K.M.; Kalbfleisch, J.D. Use of statins and incidence of dementia and cognitive impairment without dementia in a cohort study. Neurology, 2008, 71(5), 344-350.
Zandi, P.P.; Anthony, J.C.; Hayden, K.M.; Mehta, K.; Mayer, L.; Breitner, J.C. Cache County Study Investigators. Reduced incidence of AD with NSAID but not H2 receptor antagonists: The Cache County Study. Neurology, 2002, 59(6), 880-886.
Sonnen, J.A.; Larson, E.B.; Brickell, K.; Crane, P.K.; Woltjer, R.; Montine, T.J.; Craft, S. Different patterns of cerebral injury in dementia with or without diabetes. Arch. Neurol., 2009, 66, 315-322.
Lue, L.F.; Brachova, L.; Civin, W.H.; Rogers, J. Inflammation, a deposition, and neurofibrillary tangle formation as correlates of Alzheimer’s disease neurodegeneration. J. Neuropathol. Exp. Neurol., 1996, 55, 1083-1088.
Ikram, M.K.; Cheung, C.Y.; Wong, T.Y.; Chen, C.P. Retinal pathologyas biomarker for cognitive impairment and Alzheimer’s disease. J. Neurol. Neurosurg. Psychiatry, 2012, 83, 917-922.
Fiore, V.; Marci, M.; Poggi, A.; Giagulli, V.A.; Licchelli, B.; Iacoviello, M.; Guastamacchia, E.; De Pergola, G.; Triggiani, V. The association between diabetes and depression: A very disabling condition. Endocrine, 2015, 48(1), 14-24.
Triggiani, V.; Resta, F.; Guastamacchia, E.; Sabbà, C.; Licchelli, B.; Ghiyasaldin, S.; Tafaro, E. Role of antioxidants, essential fatty acids, carnitine, vitamins, phytochemicals and trace elements in the treatment of diabetes mellitus and its chronic complications. Endocr. Metab. Immune Disord. Drug Targets, 2006, 6(1), 77-93.
Resta, F.; Triggiani, V.; Barile, G.; Benigno, M.; Suppressa, P.; Giagulli, V.A.; Guastamacchia, E.; Sabbà, C. Subclinical hypothyroidism and cognitive dysfunction in the elderly. Endocr. Metab. Immune Disord. Drug Targets, 2012, 12(3), 260-267.
Giagulli, V.A.; Guastamacchia, E.; Licchelli, B.; Triggiani, V. Serum testosterone and cognitive function in ageing male: Updating the evidence. Recent Pat. Endocr. Metab. Immune Drug Discov., 2016, 10(1), 22-30.

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Article Details

Year: 2019
Page: [571 - 579]
Pages: 9
DOI: 10.2174/1871530319666190311141855
Price: $58

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