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Hippocampal interneuron loss in an APP/PS1 double mutant mouse and in Alzheimer’s disease

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Abstract

Hippocampal atrophy and neuron loss are commonly found in Alzheimer’s disease (AD). However, the underlying molecular mechanisms and the fate in the AD hippocampus of subpopulations of interneurons that express the calcium-binding proteins parvalbumin (PV) and calretinin (CR) has not yet been properly assessed. Using quantitative stereologic methods, we analyzed the regional pattern of age-related loss of PV- and CR-immunoreactive (ir) neurons in the hippocampus of mice that carry M233T/L235P knocked-in mutations in presenilin-1 (PS1) and overexpress a mutated human beta-amyloid precursor protein (APP), namely, the APPSL/PS1 KI mice, as well as in APPSL mice and PS1 KI mice. We found a loss of PV-ir neurons (40–50%) in the CA1-2, and a loss of CR-ir neurons (37–52%) in the dentate gyrus and hilus of APPSL/PS1 KI mice. Interestingly, comparable PV- and CR-ir neuron losses were observed in the dentate gyrus of postmortem brain specimens obtained from patients with AD. The loss of these interneurons in AD may have substantial functional repercussions on local inhibitory processes in the hippocampus.

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Acknowledgments

We thank Dr. G. Multhaup for generous gift of antibodies, Drs. V. Blanchard-Bregeon, L. Pradier, and T. Bayer for providing the transgenic animals, and N. Olthof, E. Barth, B. Wicinski, and H.P.J. Steinbusch for expert technical assistance. Supported by grants from the Alzheimer Forschung Initiative e.V., the Internationale Stichting Alzheimer Onderzoek, and NOW 911-06-003 (C.S. and H.W.M.S.), and by NIH grants AG02219 and AG05138 (P.R.H. and D.L.D).

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Authors and Affiliations

  1. Department of Neuroscience, Maastricht University, 6200 MD, Maastricht, The Netherlands

    Hisaaki Takahashi, Ivona Brasnjevic, Bart P. F. Rutten, Nicolien Van Der Kolk, Harry W. M. Steinbusch & Christoph Schmitz

  2. Department of Psychiatry and Neuropsychology, Maastricht University, 6200 MD, Maastricht, The Netherlands

    Hisaaki Takahashi, Ivona Brasnjevic, Bart P. F. Rutten, Nicolien Van Der Kolk, Harry W. M. Steinbusch & Christoph Schmitz

  3. Department of Molecular and Cellular Physiology, Graduate School of Medicine, Ehime University, Matsuyama, Ehime, 791-0295, Japan

    Hisaaki Takahashi

  4. European Graduate School of Neuroscience (EURON), 6200 MD, Maastricht, The Netherlands

    Ivona Brasnjevic, Bart P. F. Rutten, Nicolien Van Der Kolk, Harry W. M. Steinbusch & Christoph Schmitz

  5. Department of Pathology (Neuropathology), Mount Sinai School of Medicine, New York, NY, 10029, USA

    Daniel P. Perl

  6. Department of Neuroscience, Kastor Neurobiology of Aging Laboratories, Mount Sinai School of Medicine, 1 Gustave L. Levy Place, Box 1065, New York, NY, 10029, USA

    Daniel P. Perl, Constantin Bouras, Christoph Schmitz, Patrick R. Hof & Dara L. Dickstein

  7. Department of Psychiatry, University of Geneva School of Medicine, 1225, Geneva, Switzerland

    Constantin Bouras

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  1. Hisaaki Takahashi
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  2. Ivona Brasnjevic
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  3. Bart P. F. Rutten
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  4. Nicolien Van Der Kolk
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  7. Harry W. M. Steinbusch
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  9. Patrick R. Hof
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  10. Dara L. Dickstein
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Correspondence to Dara L. Dickstein.

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H. Takahashi and I. Brasnjevic contributed equally to this study.

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Takahashi, H., Brasnjevic, I., Rutten, B.P.F. et al. Hippocampal interneuron loss in an APP/PS1 double mutant mouse and in Alzheimer’s disease. Brain Struct Funct 214, 145–160 (2010). https://doi.org/10.1007/s00429-010-0242-4

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