Altered Expression of Diabetes-related Genes in Alzheimer's Disease Brains: the Hisayama Study

Overview

Journal Cereb Cortex

Publisher Oxford University Press

Specialty Neurology

Date 2013 Apr 19

PMID 23595620

Citations 154

Authors

Masaaki Hokama

Sugako Oka

Julio Leon

Toshiharu Ninomiya

Hiroyuki Honda

Kensuke Sasaki

Toru Iwaki

Tomoyuki Ohara

Tomio Sasaki

Frank M LaFerla

Yutaka Kiyohara

Yusaku Nakabeppu

Affiliations

Soon will be listed here.

Abstract

Diabetes mellitus (DM) is considered to be a risk factor for dementia including Alzheimer's disease (AD). However, the molecular mechanism underlying this risk is not well understood. We examined gene expression profiles in postmortem human brains donated for the Hisayama study. Three-way analysis of variance of microarray data from frontal cortex, temporal cortex, and hippocampus was performed with the presence/absence of AD and vascular dementia, and sex, as factors. Comparative analyses of expression changes in the brains of AD patients and a mouse model of AD were also performed. Relevant changes in gene expression identified by microarray analysis were validated by quantitative real-time reverse-transcription polymerase chain reaction and western blotting. The hippocampi of AD brains showed the most significant alteration in gene expression profile. Genes involved in noninsulin-dependent DM and obesity were significantly altered in both AD brains and the AD mouse model, as were genes related to psychiatric disorders and AD. The alterations in the expression profiles of DM-related genes in AD brains were independent of peripheral DM-related abnormalities. These results indicate that altered expression of genes related to DM in AD brains is a result of AD pathology, which may thereby be exacerbated by peripheral insulin resistance or DM.

Citing Articles

Biomarker Identification for Alzheimer's Disease Using a Multi-Filter Gene Selection Approach.

Pashaei E, Pashaei E, Aydin N Int J Mol Sci. 2025; 26(5).

PMID: 40076442 PMC: 11898513. DOI: 10.3390/ijms26051816.

The neuroimmune nexus: unraveling the role of the mtDNA-cGAS-STING signal pathway in Alzheimer's disease.

Quan S, Fu X, Cai H, Ren Z, Xu Y, Jia L Mol Neurodegener. 2025; 20(1):25.

PMID: 40038765 PMC: 11877805. DOI: 10.1186/s13024-025-00815-2.

Association of late-life variability in hemoglobin A1C with postmortem neuropathologies.

Biswas R, Capuano A, Mehta R, Bennett D, Arvanitakis Z Alzheimers Dement. 2025; 21(2):e14471.

PMID: 39968681 PMC: 11863718. DOI: 10.1002/alz.14471.

EBP1 potentiates amyloid β pathology by regulating γ-secretase.

Kim B, Hwang I, Ko H, Kim Y, Kim H, Seo S Nat Aging. 2025; .

PMID: 39779912 DOI: 10.1038/s43587-024-00790-1.

Chronological Dynamics of Neuroinflammatory Responses in a High-Fat Diet Mouse Model.

Bae H, Shin S, Lee J, Choi S, Kwon E Int J Mol Sci. 2024; 25(23).

PMID: 39684545 PMC: 11640818. DOI: 10.3390/ijms252312834.

References

Mirra S, HEYMAN A, McKeel D, SUMI S, Crain B, Brownlee L . The Consortium to Establish a Registry for Alzheimer's Disease (CERAD). Part II. Standardization of the neuropathologic assessment of Alzheimer's disease. Neurology. 1991; 41(4):479-86. DOI: 10.1212/wnl.41.4.479. View

Gunstad J, Strain G, Devlin M, Wing R, Cohen R, Paul R . Improved memory function 12 weeks after bariatric surgery. Surg Obes Relat Dis. 2010; 7(4):465-72. PMC: 3117085. DOI: 10.1016/j.soard.2010.09.015. View

Asanoma K, Kubota K, Chakraborty D, Renaud S, Wake N, Fukushima K . SATB homeobox proteins regulate trophoblast stem cell renewal and differentiation. J Biol Chem. 2011; 287(3):2257-68. PMC: 3265903. DOI: 10.1074/jbc.M111.287128. View

Abderrahmani A, Niederhauser G, Plaisance V, Roehrich M, Lenain V, Coppola T . Complexin I regulates glucose-induced secretion in pancreatic beta-cells. J Cell Sci. 2004; 117(Pt 11):2239-47. DOI: 10.1242/jcs.01041. View

Steen E, Terry B, Rivera E, Cannon J, Neely T, Tavares R . 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(1):63-80. DOI: 10.3233/jad-2005-7107. View

De Felice F, Vieira M, Bomfim T, Decker H, Velasco P, Lambert M . Protection of synapses against Alzheimer's-linked toxins: insulin signaling prevents the pathogenic binding of Abeta oligomers. Proc Natl Acad Sci U S A. 2009; 106(6):1971-6. PMC: 2634809. DOI: 10.1073/pnas.0809158106. View

Sekita A, Ninomiya T, Tanizaki Y, Doi Y, Hata J, Yonemoto K . Trends in prevalence of Alzheimer's disease and vascular dementia in a Japanese community: the Hisayama Study. Acta Psychiatr Scand. 2010; 122(4):319-25. DOI: 10.1111/j.1600-0447.2010.01587.x. View

Watson E, Hahm S, Mizuno T, Windsor J, Montgomery C, Scherer P . VGF ablation blocks the development of hyperinsulinemia and hyperglycemia in several mouse models of obesity. Endocrinology. 2005; 146(12):5151-63. DOI: 10.1210/en.2005-0588. View

Miele C, Rochford J, Filippa N, Giorgetti-Peraldi S, Van Obberghen E . Insulin and insulin-like growth factor-I induce vascular endothelial growth factor mRNA expression via different signaling pathways. J Biol Chem. 2000; 275(28):21695-702. DOI: 10.1074/jbc.M000805200. View

10.

Colangelo V, Schurr J, Ball M, Pelaez R, Bazan N, Lukiw W . Gene expression profiling of 12633 genes in Alzheimer hippocampal CA1: transcription and neurotrophic factor down-regulation and up-regulation of apoptotic and pro-inflammatory signaling. J Neurosci Res. 2002; 70(3):462-73. DOI: 10.1002/jnr.10351. View

11.

Ferri C, Prince M, Brayne C, Brodaty H, Fratiglioni L, Ganguli M . Global prevalence of dementia: a Delphi consensus study. Lancet. 2005; 366(9503):2112-7. PMC: 2850264. DOI: 10.1016/S0140-6736(05)67889-0. View

12.

Sherin A, Peeyush K, Naijil G, Chinthu R, Paulose C . Hypoglycemia induced behavioural deficit and decreased GABA receptor, CREB expression in the cerebellum of streptozoticin induced diabetic rats. Brain Res Bull. 2010; 83(6):360-6. DOI: 10.1016/j.brainresbull.2010.09.004. View

13.

Craft S, Baker L, Montine T, Minoshima S, Watson G, Claxton A . Intranasal insulin therapy for Alzheimer disease and amnestic mild cognitive impairment: a pilot clinical trial. Arch Neurol. 2011; 69(1):29-38. PMC: 3260944. DOI: 10.1001/archneurol.2011.233. View

14.

Fafalios A, Ma J, Tan X, Stoops J, Luo J, DeFrances M . A hepatocyte growth factor receptor (Met)-insulin receptor hybrid governs hepatic glucose metabolism. Nat Med. 2011; 17(12):1577-84. PMC: 3233634. DOI: 10.1038/nm.2531. View

15.

Uittenbogaard M, Baxter K, Chiaramello A . The neurogenic basic helix-loop-helix transcription factor NeuroD6 confers tolerance to oxidative stress by triggering an antioxidant response and sustaining the mitochondrial biomass. ASN Neuro. 2010; 2(2):e00034. PMC: 2874871. DOI: 10.1042/AN20100005. View

16.

Matsuzaki T, Sasaki K, Tanizaki Y, Hata J, Fujimi K, Matsui Y . Insulin resistance is associated with the pathology of Alzheimer disease: the Hisayama study. Neurology. 2010; 75(9):764-70. DOI: 10.1212/WNL.0b013e3181eee25f. View

17.

Takeda S, Sato N, Uchio-Yamada K, Sawada K, Kunieda T, Takeuchi D . Diabetes-accelerated memory dysfunction via cerebrovascular inflammation and Abeta deposition in an Alzheimer mouse model with diabetes. Proc Natl Acad Sci U S A. 2010; 107(15):7036-41. PMC: 2872449. DOI: 10.1073/pnas.1000645107. View

18.

Katsuki S . Epidemiological and clinicopathological study on cerebrovascular disease in Japan. Prog Brain Res. 1966; 21:64-89. DOI: 10.1016/s0079-6123(08)64226-0. View

19.

Seidah N, Benjannet S, Hamelin J, Mamarbachi A, Basak A, Marcinkiewicz J . The subtilisin/kexin family of precursor convertases. Emphasis on PC1, PC2/7B2, POMC and the novel enzyme SKI-1. Ann N Y Acad Sci. 2000; 885:57-74. DOI: 10.1111/j.1749-6632.1999.tb08665.x. View

20.

Tan M, Chua W, Esiri M, Smith A, Vinters H, Lai M . Genome wide profiling of altered gene expression in the neocortex of Alzheimer's disease. J Neurosci Res. 2009; 88(6):1157-69. DOI: 10.1002/jnr.22290. View