Limited Alzheimer-type neurodegeneration in experimental obesity and type 2 diabetes mellitus

J Alzheimers Dis. 2008 Sep;15(1):29-44. doi: 10.3233/jad-2008-15103.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actins / metabolism
  • Adaptor Proteins, Signal Transducing / metabolism
  • Aldehydes / metabolism
  • Alzheimer Disease / genetics
  • Alzheimer Disease / metabolism
  • Alzheimer Disease / pathology*
  • Amyloid beta-Peptides / metabolism
  • Animals
  • Atrophy / metabolism
  • Atrophy / pathology
  • Brain / metabolism
  • Brain / pathology*
  • DNA Primers / genetics
  • Diabetes Mellitus, Type 2 / metabolism*
  • Enzyme-Linked Immunosorbent Assay
  • Gene Expression / genetics
  • Glial Fibrillary Acidic Protein / metabolism
  • Insulin Receptor Substrate Proteins
  • Insulin Resistance / physiology
  • Insulin-Like Growth Factor I / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Nerve Degeneration / genetics
  • Nerve Degeneration / metabolism
  • Nerve Degeneration / pathology*
  • Obesity / metabolism*
  • RNA, Messenger / genetics
  • Reverse Transcriptase Polymerase Chain Reaction
  • Ubiquitin / metabolism


  • Actins
  • Adaptor Proteins, Signal Transducing
  • Aldehydes
  • Amyloid beta-Peptides
  • DNA Primers
  • Glial Fibrillary Acidic Protein
  • Insulin Receptor Substrate Proteins
  • Irs1 protein, mouse
  • RNA, Messenger
  • Ubiquitin
  • Insulin-Like Growth Factor I
  • 4-hydroxy-2-nonenal