AGE

, Volume 29, Issue 2–3, pp 87–96

Neuropathological quantification of dtg APP/PS1: neuroimaging, stereology, and biochemistry

  • Kebreten F. Manaye
  • Paul C. Wang
  • Jahn N. O’Neil
  • Sophia Y. Huang
  • Tao Xu
  • De-Liang Lei
  • Yousef Tizabi
  • Mary Ann Ottinger
  • Donald K. Ingram
  • Peter R. Mouton
Article

Abstract

Murine models that mimic the neuropathology of Alzheimer’s disease (AD) have the potential to provide insight into the pathogenesis of the disease and lead to new strategies for the therapeutic management of afflicted patients. We used magnetic resonance imaging (MRI), design-based stereology, and high performance liquid chromatography (HPLC) to assess the age-related neuropathology in double transgenic mice that overexpress two AD-related proteins—amyloid precursor protein (APP) and presenilin 1 (PS1)—and age- and gender-matched wild-type (WT) controls. In mice ranging in age from 4–28 months, total volumes of the hippocampal formation (VHF) and whole brain (Vbrain) were quantified by the Cavalieri-point counting method on a systematic-random sample of coronal T2-weighted MRI images; the same stereological methods were used to quantify VHF and Vbrain after perfusion and histological processing. To assess changes in AD-type beta-amyloid (Aβ) plaques, sections from the hippocampal formation and amylgdaloid complex of mice aged 5, 12, and 15 months were stained by Congo Red histochemistry. In aged mice with large numbers of amyloid plaques, systematic-random samples of sections were stained by GFAP immunocytochemistry to assess gender and genotype effects on total numbers of astrocytes. In addition, levels of norepinephrine (NE), dopamine (DA), serotonin (5-HT) and 5-HT metabolites were assayed by HPLC in fresh-frozen samples from neocortex, striatum, hippocampus, and brainstem. We confirmed age-related increases in amyloid plaques, beginning with a few plaques at 5 months of age and increasing densities by 12 and 15 months. At 15 months of age, there were robust genotype effects, but no gender effects, on GFAP-immunopositive astrocytes in the amygdaloid complex and hippocampus. There were no effects on monoamine levels in all brain regions examined, and no volume changes in hippocampal formation or whole brain as quantified on either neuroimages or tissue sections. Strong correlations were present between volume estimates from MRI images and histological sections, with about 85% reduction in mean VHF or mean Vbrain between MRI and processed histological sections. In summary, these findings show that the double transgenic expression of AD-type mutations is associated with age-related increases in amyloid plaques and astrocytosis; however, this model does not recapitulate the cortical atrophy or neurochemical changes that are characteristic of AD.

Keywords

MRI Alzheimer’s disease Hippocampal formation Amygdala Unbiased stereology 

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Copyright information

© American Aging Association, Media, PA, USA 2007

Authors and Affiliations

  • Kebreten F. Manaye
    • 1
  • Paul C. Wang
    • 2
  • Jahn N. O’Neil
    • 1
    • 8
  • Sophia Y. Huang
    • 2
  • Tao Xu
    • 1
  • De-Liang Lei
    • 1
  • Yousef Tizabi
    • 3
  • Mary Ann Ottinger
    • 4
    • 5
  • Donald K. Ingram
    • 5
    • 6
  • Peter R. Mouton
    • 7
  1. 1.Department of Physiology and BiophysicsHoward University College of MedicineWashingtonUSA
  2. 2.Department of RadiologyHoward University College of MedicineWashingtonUSA
  3. 3.Department of PharmacologyHoward University College of MedicineWashingtonUSA
  4. 4.University of MarylandCollege ParkUSA
  5. 5.Laboratory of Experimental GerontologyNational Institute on Aging, NIHBaltimoreUSA
  6. 6.Nutritional Neuroscience and Aging LaboratoryLouisiana State UniversityBaton RougeUSA
  7. 7.Stereology Resource CenterChesterUSA
  8. 8.School of MedicineJohns Hopkins UniversityBaltimoreUSA

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