Loss of calbindin-D28k from aging human cholinergic basal forebrain: Relation to neuronal loss

Authors

  • Changiz Geula,

    Corresponding author
    1. Laboratory for Neurodegenerative and Aging Research, Section of Gerontology, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215
    2. Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115
    3. Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215
    • Laboratory for Neurodegenerative and Aging Research, Beth Israel Deaconess Medical Center, Burlington Research Building, 330 Brookline Ave., Boston, MA 02215
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  • Jing Bu,

    1. Laboratory for Neurodegenerative and Aging Research, Section of Gerontology, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215
    2. Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115
    3. Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215
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  • Nicholas Nagykery,

    1. Laboratory for Neurodegenerative and Aging Research, Section of Gerontology, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215
    2. Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115
    3. Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215
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  • Leonard F.M. Scinto,

    1. Department of Neurology, Harvard Medical School, Boston, Massachusetts 02115
    2. Brigham and Women's Hospital, Boston, Massachusetts 02115
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  • Jennifer Chan,

    1. Department of Neurology, Harvard Medical School, Boston, Massachusetts 02115
    2. Brigham and Women's Hospital, Boston, Massachusetts 02115
    3. Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115
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  • Jeffrey Joseph,

    1. Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215
    2. Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115
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  • Robert Parker,

    1. Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115
    2. Biometrics Center, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215
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  • Chuang-Kuo Wu

    1. Department of Neuroscience, University of California at San Diego, La Jolla, California 92093
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Abstract

Cholinergic neurons of the basal forebrain (BFCN) are selectively vulnerable in neurodegenerative disorders of the elderly, particularly in Alzheimer's disease (AD). We investigated age-related changes in the BFCN that may serve as a substrate for this vulnerability. We report a substantial and selective age-related loss of the calcium binding protein calbindin-D28K (CB) from the human BFCN. Unbiased stereological estimation indicated that, in individuals under age 65 years, 72% of the choline acetyltransferase (ChAT)-positive BFCN contained CB immunoreactivity. In individuals over age 65 years, only 28% of the BFCN contained CB immunoreactivity, a dramatic loss of 61%. Similar results were obtained using neuronal counts from matching single- or double-stained sections in a larger cohort. The loss of CB immunoreactivity was neurochemically specific. No age-related changes were observed in the number of ChAT- or low-affinity nerve growth factor receptor (p75NTR)-immunoreactive profiles. The loss of CB was greatest in very old individuals, in whom a small loss of BFCN was observed. Furthermore, the loss of CB displayed the same pattern as the loss of BFCN in AD and was more substantial in the posterior compared with the anterior BFCN sector, suggesting a role for CB in the selective vulnerability of BFCN in AD. The depletion of CB from the BFCN is likely to deprive these neurons of the capacity to buffer high levels of intracellular Ca2+ and thus to leave them vulnerable to pathological processes, such as those in neurodegenerative disorders, which can cause increased intracellular Ca2+, thus leading to their degeneration. J. Comp. Neurol. 455:249–259, 2003. © 2002 Wiley-Liss, Inc.

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