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Age-related loss of calcium buffering and selective neuronal vulnerability in Alzheimer’s disease

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Abstract

The reasons for the selective vulnerability of distinct neuronal populations in neurodegenerative disorders are unknown. The cholinergic neurons of the basal forebrain are vulnerable to pathology and loss early in Alzheimer’s disease and in a number of other neurodegenerative disorders of the elderly. In the primate, including man, these neurons are rich in the calcium buffer calbindin-D28K. Here, we confirm that these neurons undergo a substantial loss of calbindin in the course of normal aging and report a further loss of calbindin in Alzheimer’s disease both at the level of RNA and protein. Significantly, cholinergic neurons that had lost their calbindin in the course of normal aging were those that selectively degenerated in Alzheimer’s disease. Furthermore, calbindin-containing neurons were virtually resistant to the process of tangle formation, a hallmark of the disease. We conclude that the loss of calcium buffering capacity in these neurons and the resultant pathological increase in intracellular calcium are permissive to tangle formation and degeneration.

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Acknowledgments

We are grateful to Girgis Girgis and Katherine Gasho for expert technical assistance. This work was supported in part by a Zenith Fellows Award (C.G.) from the Alzheimer’s Association; and by grants from the National Institute on Aging (AG014706 and AG027141). A portion of the tissue used in these studies was received from the Northwestern University (AG013854) and Massachusetts General Hospital (AG005134) Alzheimer’s Disease Centers.

Conflict of interest

The authors declare that they have no conflict of interest.

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Author notes

  1. Jing Bu

    Present address: Berkshire Medical Center, Pittsfield, MA, USA

Authors and Affiliations

  1. Laboratory for Cognitive and Molecular Morphometry, Cognitive Neurology and Alzheimer’s Disease Center, Northwestern University Feinberg School of Medicine, 320 East Superior Street, Searle 11-467, Chicago, IL, 60611, USA

    David Riascos, Dianne de Leon, Alaina Baker-Nigh & Changiz Geula

  2. Department of Medicine, Harvard Medical School and Division of Gerontology, Beth Israel Deaconess Medical Center, Boston, MA, 02215, USA

    Alexander Nicholas & Jing Bu

  3. Precision Biosystems, Mansfield, MA, 02048, USA

    Rustam Yukhananov

  4. Department of Neurology, Texas Tech University HSC School of Medicine, Lubbock, TX, 79430, USA

    Chuang-Kuo Wu

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  1. David Riascos
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Corresponding author

Correspondence to Changiz Geula.

Additional information

D. Riascos, D. de Leon and A. Baker-Nigh contributed equally to the work reported here.

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Riascos, D., de Leon, D., Baker-Nigh, A. et al. Age-related loss of calcium buffering and selective neuronal vulnerability in Alzheimer’s disease. Acta Neuropathol 122, 565–576 (2011). https://doi.org/10.1007/s00401-011-0865-4

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  • DOI: https://doi.org/10.1007/s00401-011-0865-4

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