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Early involvement of small inhibitory cortical interneurons in Alzheimer’s disease

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Abstract

Work on acute models of cortical injury has revealed a population of small GABAergic interneurons that are induced to increase their low constitutive expression of neuronal nitric oxide (NO) synthase (nNOS). In some cases, this activation may play a role in NO-mediated degeneration of pyramidal neurons. In this report, we explore the anatomy of various classes of cortical nNOS (+) (nitrergic) neurons, with emphasis on small interneurons, in the medial temporal lobe of subjects with Alzheimer’s disease (AD) from two well-characterized cohorts, the Baltimore Longitudinal Study on Aging (BLSA) and the Religious Order Study (ROS). We find that small calbindin (+) cortical interneurons are induced to high levels of NADPHd/nNOS reactivity early in AD and abound in areas with emerging neurofibrillary pathology, that is, in entorhinal cortex in the beginning of the limbic stage of Braak, in hippocampal CA1 in the mature limbic stage and in temporal neocortex in the late limbic stage. This pattern was robust and significant in the younger of the two AD cohorts studied (BLSA), but persisted as a trend in the older cohort (ROS). In optimally prepared material, we find a significant correlation between numbers of these interneurons and markers of neuronal cell death, for example, caspase-3 activation. Our results show that small cortical inhibitory interneurons represent an extensive signaling system that is induced to higher levels of NADPHd/nNOS expression early in the paralimbic–limbic–neocortical sequence of AD progression. We propose that nNOS/NO signaling initiated in these interneurons can serve as a marker of early cortical injury in AD. The specific role played by inhibitory interneurons and NO in the elaboration of specific neuropathologies associated with AD, that is, Aβ and neurofibrillary deposits and cell death deserves further exploration in experimental animal models.

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Acknowledgments

We thank Ms Annie Welsh for her expert technical assistance. This work was supported by NIH grants RO1 AG16263 and 3 P50 AG05146.

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Authors and Affiliations

  1. Department of Pathology, Division of Neuropathology, The Johns Hopkins Medical Institutions, Baltimore, MD, USA

    Vassilis E. Koliatsos, Aleksandar Kecojevic, Juan C. Troncoso & Myriam C. Gastard

  2. Department of Neurology, The Johns Hopkins Medical Institutions, Baltimore, MD, USA

    Vassilis E. Koliatsos & Juan C. Troncoso

  3. Department of Neuroscience, The Johns Hopkins Medical Institutions, Baltimore, MD, USA

    Vassilis E. Koliatsos

  4. Department of Psychiatry and Behavioral Sciences, The Johns Hopkins Medical Institutions, Baltimore, MD, USA

    Vassilis E. Koliatsos

  5. Rush Alzheimer’s Disease Center, Rush University Medical Center, Chicago, IL, USA

    David A. Bennett & Julie A. Schneider

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  1. Vassilis E. Koliatsos
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Correspondence to Vassilis E. Koliatsos.

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Koliatsos, V.E., Kecojevic, A., Troncoso, J.C. et al. Early involvement of small inhibitory cortical interneurons in Alzheimer’s disease. Acta Neuropathol 112, 147–162 (2006). https://doi.org/10.1007/s00401-006-0068-6

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