title: Limited Alzheimer-type neurodegeneration in experimental obesity and type 2 diabetes mellitus.
abstract: Alzheimer's disease (AD) is associated with brain insulin resistance and insulin deficiency, whereas Type 2 diabetes mellitus (T2DM) is associated with peripheral insulin resistance. This study assesses the degree to which T2DM causes AD-type neurodegeneration. In a C57BL/6 mouse model of obesity and T2DM, we characterized the histopathology, gene expression, and insulin and insulin-like growth factor (IGF)-receptor binding in temporal lobe. High fat diet (HFD) feeding for 16 weeks doubled mean body weight, caused T2DM, and marginally reduced mean brain weight. These effects were associated with significantly increased levels of tau, IGF-I receptor, insulin receptor substrate-1 (IRS-1), IRS-4, ubiquitin, glial fibrillary acidic protein, and 4-hydroxynonenol, and decreased expression of beta-actin. HFD feeding also caused brain insulin resistance manifested by reduced BMAX for insulin receptor binding, and modestly increased brain insulin gene expression. However, HFD-fed mouse brains did not exhibit AD histopathology, increases in amyloid-beta or phospho-tau, or impairments in IGF signaling or acetylcholine homeostasis. Obesity and T2DM cause brain atrophy with insulin resistance, oxidative stress, and cytoskeleton degradation, but the absence of many features that typify AD suggests that obesity and T2DM may contribute to, but are not sufficient to cause AD.
authors.affiliation: Department of Medicine, Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, RI 02903, USA.
authors.forename: Natalie
authors.initials: N
authors.lastname: Moroz
authors.forename: Ming
authors.initials: M
authors.lastname: Tong
authors.forename: Lisa
authors.initials: L
authors.lastname: Longato
authors.forename: Haiyan
authors.initials: H
authors.lastname: Xu
authors.forename: Suzanne M
authors.initials: SM
authors.lastname: de la Monte
mesh_terms: D000199:Actins / Q000378:metabolism; D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000447:Aldehydes / Q000378:metabolism; D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D001284:Atrophy / Q000378:metabolism / Q000473:pathology; D001921:Brain / Q000378:metabolism / Q000473:pathology*; D017931:DNA Primers / Q000235:genetics; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D015870:Gene Expression / Q000235:genetics; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D055504:Insulin Receptor Substrate Proteins; D007333:Insulin Resistance / Q000502:physiology; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009410:Nerve Degeneration / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D009765:Obesity / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D025801:Ubiquitin / Q000378:metabolism
chemical_list: D000199:Actins; D048868:Adaptor Proteins, Signal Transducing; D000447:Aldehydes; D016229:Amyloid beta-Peptides; D017931:DNA Primers; D005904:Glial Fibrillary Acidic Protein; D055504:Insulin Receptor Substrate Proteins; C526295:Irs1 protein, mouse; D012333:RNA, Messenger; D025801:Ubiquitin; D007334:Insulin-Like Growth Factor I; C027576:4-hydroxy-2-nonenal
references.citation: Cell Mol Life Sci. 2003 Dec;60(12):2679-91
references.pmid: 14685691
references.citation: Curr Neurol Neurosci Rep. 2007 Sep;7(5):373-80
references.pmid: 17764626
references.citation: Int J Obes (Lond). 2008 Feb;32(2):275-82
references.pmid: 17848936
references.citation: J Clin Invest. 2003 Dec;112(12):1821-30
references.pmid: 14679177
references.citation: Diabetes Care. 2006 Oct;29(10):2268-74
references.pmid: 17003305
references.citation: Cell Mol Life Sci. 2006 Sep;63(17):2039-56
references.pmid: 16909201
references.citation: Curr Opin Psychiatry. 2007 Jul;20(4):380-5
references.pmid: 17551353
references.citation: Diabetes. 2004 Nov;53(11):3024-9
references.pmid: 15504987
references.citation: Neurobiol Aging. 2006 Jan;27(1):38-41
references.pmid: 16298239
references.citation: Arch Neurol. 2007 Apr;64(4):570-5
references.pmid: 17420320
references.citation: Prog Neurobiol. 2004 Dec;74(5):249-70
references.pmid: 15582222
references.citation: Alzheimer Dis Assoc Disord. 2006 Oct-Dec;20(4):298-301
references.pmid: 17132977
references.citation: Curr Alzheimer Res. 2004 Feb;1(1):47-54
references.pmid: 15975085
references.citation: J Neuroimmunol. 1999 Jan 1;93(1-2):182-93
references.pmid: 10378882
references.citation: Biochim Biophys Acta. 2000 Jul 26;1502(1):145-57
references.pmid: 10899440
references.citation: Exp Neurol. 2006 Jun;199(2):265-73
references.pmid: 16515786
references.citation: Neurology. 2008 Feb 5;70(6):440-8
references.pmid: 17942819
references.citation: Int Rev Psychiatry. 2005 Dec;17(6):503-14
references.pmid: 16401549
references.citation: Neurology. 2005 Aug 23;65(4):545-51
references.pmid: 16116114
references.citation: Biochem Mol Biol Int. 1998 Jan;44(1):1-7
references.pmid: 9503142
references.citation: J Alzheimers Dis. 2006 Mar;9(1):13-33
references.pmid: 16627931
references.citation: Curr Diab Rep. 2005 Feb;5(1):59-63
references.pmid: 15663919
references.citation: Behav Neurosci. 1996 Jun;110(3):451-9
references.pmid: 8888990
references.citation: Int J Dev Neurosci. 2006 Apr-May;24(2-3):167-76
references.pmid: 16472958
references.citation: Neurobiol Aging. 1999 Jan-Feb;20(1):47-51
references.pmid: 10466892
references.citation: J Alzheimers Dis. 1998 Dec;1(2):119-134
references.pmid: 12214008
references.citation: J Nutr Biochem. 2008 May;19(5):277-86
references.pmid: 18054218
references.citation: Diabetes Metab. 2006 Nov;32(5 Pt 1):403-14
references.pmid: 17110895
references.citation: Annu Rev Public Health. 2004;25:1-24
references.pmid: 15015910
references.citation: J Alzheimers Dis. 2005 Feb;7(1):63-80
references.pmid: 15750215
references.citation: Diabetes. 2004 Feb;53(2):474-81
references.pmid: 14747300
references.citation: Curr Alzheimer Res. 2007 Apr;4(2):153-7
references.pmid: 17430240
references.citation: Curr Alzheimer Res. 2007 Apr;4(2):147-52
references.pmid: 17430239
references.citation: Neurobiol Aging. 2006 Mar;27(3):451-8
references.pmid: 15964100
references.citation: Neurology. 2004 Nov 23;63(10):1882-91
references.pmid: 15557506
references.citation: J Alzheimers Dis. 2005 Feb;7(1):45-61
references.pmid: 15750214
references.citation: Neurobiol Aging. 2005 Dec;26 Suppl 1:65-9
references.pmid: 16266773
references.citation: Curr Atheroscler Rep. 2004 Jul;6(4):261-6
references.pmid: 15191699
references.citation: J Neural Transm (Vienna). 1999;106(11-12):1171-88
references.pmid: 10651112
references.citation: J Alzheimers Dis. 2005 Dec;8(3):247-68
references.pmid: 16340083
references.citation: Clin Liver Dis. 2007 Feb;11(1):105-17, ix
references.pmid: 17544974
references.citation: Am J Clin Pathol. 2007 Nov;128(5):837-47
references.pmid: 17951208
references.citation: Curr Alzheimer Res. 2007 Apr;4(2):159-64
references.pmid: 17430241
references.citation: J Mol Med (Berl). 2004 Aug;82(8):510-29
references.pmid: 15175861
references.citation: J Gastroenterol Hepatol. 2007 Jun;22 Suppl 1:S20-7
references.pmid: 17567459
references.citation: J Biol Chem. 1997 Aug 1;272(31):19547-53
references.pmid: 9235959
references.citation: Nat Clin Pract Neurol. 2006 Mar;2(3):159-66
references.pmid: 16932542
references.citation: Behav Neurosci. 2005 Oct;119(5):1389-95
references.pmid: 16300445
references.citation: Diabetes. 2007 Jan;56(1):211-6
references.pmid: 17192484
references.citation: J Neurol Sci. 2006 Jun 15;245(1-2):21-33
references.pmid: 16631207
references.citation: Neurobiol Aging. 2005 Dec;26 Suppl 1:46-9
references.pmid: 16219391
references.citation: Clin Nutr. 2007 Aug;26(4):409-15
references.pmid: 17449148
references.citation: J Alzheimers Dis. 2006 Sep;10(1):89-109
references.pmid: 16988486
references.citation: Curr Alzheimer Res. 2007 Apr;4(2):103-9
references.pmid: 17430231
references.citation: Neuroendocrinology. 2007;86(2):136-42
references.pmid: 17643054
references.citation: J Neurosci Methods. 2004 Jan 15;132(1):101-7
references.pmid: 14687679
references.citation: Recenti Prog Med. 2004 Nov;95(11):535-45
references.pmid: 15598092
references.citation: Diabetes. 2005 Jan;54(1):212-9
references.pmid: 15616031
references.citation: Psychoneuroendocrinology. 2004 Nov;29(10):1326-34
references.pmid: 15288712
references.citation: J Neural Transm (Vienna). 2004 Mar;111(3):347-66
references.pmid: 14991459
references.citation: J Neurol Neurosurg Psychiatry. 2007 Dec;78(12):1325-30
references.pmid: 17470472
references.citation: Acta Neuropathol. 2002 May;103(5):444-52
references.pmid: 11935259
references.citation: Stroke. 2005 Jul;36(7):1551-6
references.pmid: 15933257
references.citation: Diabetes Metab. 2008 Feb;34(1):2-11
references.pmid: 18093861
references.citation: Mol Biol Cell. 2007 Jan;18(1):201-10
references.pmid: 17093061
references.citation: Neurotoxicol Teratol. 2002 Sep-Oct;24(5):695-701
references.pmid: 12200200
references.citation: Mol Psychiatry. 2006 Aug;11(8):721-36
references.pmid: 16786033
references.citation: Alcohol Clin Exp Res. 2007 Sep;31(9):1558-73
references.pmid: 17645580
references.citation: J Cell Biol. 2001 Feb 5;152(3):579-94
references.pmid: 11157984
references.citation: J Alzheimers Dis. 2007 Mar;11(1):45-51
references.pmid: 17361034
references.citation: J Alzheimers Dis. 2006 Dec;10(4):391-7
references.pmid: 17183150