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

AGE volume 29, pages 87–96 (2007)Cite this 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 (V HF) and whole brain (V brain) 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 V HF and V brain 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 V HF or mean V brain 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.

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Acknowledgements

The authors would like to recognize the Public Health Service for funding support for these studies (SNRP2U54NS039407-06, NIH grant MH076541-02A1, RCMI/NCRR/NIH G12RR03048, US Army USAMRMC W81XWH-05-1-0291, NIH MHIRT 9T 37-MD001582-08) and the technical support of Armand Oei and Huafu Song in the laboratory of Biomedical NMR at the Howard University School of Medicine. The authors also appreciate the support of Nikki Thompson for the monoamine assays through the Maryland Agriculture Experiment Station of the University of Maryland.

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Affiliations

  1. Department of Physiology and Biophysics, Howard University College of Medicine, 520 W. Street, NW, Suite 2305, Adams Bldg., Washington, DC, 20059, USA

    Kebreten F. Manaye, Jahn N. O’Neil, Tao Xu & De-Liang Lei

  2. Department of Radiology, Howard University College of Medicine, Washington, DC, USA

    Paul C. Wang & Sophia Y. Huang

  3. Department of Pharmacology, Howard University College of Medicine, Washington, DC, USA

    Yousef Tizabi

  4. University of Maryland, College Park, MD, USA

    Mary Ann Ottinger

  5. Laboratory of Experimental Gerontology, National Institute on Aging, NIH, Baltimore, MD, USA

    Mary Ann Ottinger & Donald K. Ingram

  6. Nutritional Neuroscience and Aging Laboratory, Louisiana State University, Baton Rouge, LA, USA

    Donald K. Ingram

  7. Stereology Resource Center, Chester, MD, USA

    Peter R. Mouton

  8. School of Medicine, Johns Hopkins University, Baltimore, MD, USA

    Jahn N. O’Neil

Authors
  1. Kebreten F. Manaye
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  2. Paul C. Wang
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  3. Jahn N. O’Neil
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  4. Sophia Y. Huang
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  5. Tao Xu
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  6. De-Liang Lei
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  7. Yousef Tizabi
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  8. Mary Ann Ottinger
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  9. Donald K. Ingram
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  10. Peter R. Mouton
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Correspondence to Kebreten F. Manaye.

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Manaye, K.F., Wang, P.C., O’Neil, J.N. et al. Neuropathological quantification of dtg APP/PS1: neuroimaging, stereology, and biochemistry. AGE 29, 87–96 (2007). https://doi.org/10.1007/s11357-007-9035-y

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  • DOI: https://doi.org/10.1007/s11357-007-9035-y

Keywords

  • MRI
  • Alzheimer’s disease
  • Hippocampal formation
  • Amygdala
  • Unbiased stereology