Diabetes exacerbates amyloid and neurovascular pathology in aging-accelerated mice

Aging Cell. 2012 Dec;11(6):1017-26. doi: 10.1111/acel.12002. Epub 2012 Oct 1.


Mounting evidence supports a link between diabetes, cognitive dysfunction, and aging. However, the physiological mechanisms by which diabetes impacts brain function and cognition are not fully understood. To determine how diabetes contributes to cognitive dysfunction and age-associated pathology, we used streptozotocin to induce type 1 diabetes (T1D) in senescence-accelerated prone 8 (SAMP8) and senescence-resistant 1 (SAMR1) mice. Contextual fear conditioning demonstrated that T1D resulted in the development of cognitive deficits in SAMR1 mice similar to those seen in age-matched, nondiabetic SAMP8 mice. No further cognitive deficits were observed when the SAMP8 mice were made diabetic. T1D dramatically increased Aβ and glial fibrillary acidic protein immunoreactivity in the hippocampus of SAMP8 mice and to a lesser extent in age-matched SAMR1 mice. Further analysis revealed aggregated Aβ within astrocyte processes surrounding vessels. Western blot analyses from T1D SAMP8 mice showed elevated amyloid precursor protein processing and protein glycation along with increased inflammation. T1D elevated tau phosphorylation in the SAMR1 mice but did not further increase it in the SAMP8 mice where it was already significantly higher. These data suggest that aberrant glucose metabolism potentiates the aging phenotype in old mice and contributes to early stage central nervous system pathology in younger animals.

Publication types

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

MeSH terms

  • Age Factors
  • Aging / genetics*
  • Aging / metabolism
  • Aging / pathology
  • Amyloid beta-Peptides / genetics*
  • Amyloid beta-Peptides / metabolism
  • Animals
  • Astrocytes / metabolism
  • Astrocytes / pathology*
  • Blood Vessels / metabolism
  • Blood Vessels / pathology*
  • Cognition Disorders / genetics*
  • Cognition Disorders / metabolism
  • Cognition Disorders / pathology
  • Diabetes Mellitus, Experimental / chemically induced
  • Diabetes Mellitus, Experimental / genetics*
  • Diabetes Mellitus, Experimental / metabolism
  • Diabetes Mellitus, Experimental / pathology
  • Gene Expression
  • Glial Fibrillary Acidic Protein / genetics
  • Glial Fibrillary Acidic Protein / metabolism
  • Glycation End Products, Advanced / metabolism
  • Glycosylation
  • Hippocampus / metabolism
  • Hippocampus / pathology*
  • Humans
  • Male
  • Mice
  • Mice, Transgenic
  • Phosphorylation
  • Streptozocin
  • tau Proteins / genetics
  • tau Proteins / metabolism


  • Amyloid beta-Peptides
  • Glial Fibrillary Acidic Protein
  • Glycation End Products, Advanced
  • tau Proteins
  • Streptozocin