Journal of Molecular Neuroscience

, Volume 20, Issue 3, pp 357–362 | Cite as

Calpain inhibitors, a treatment for alzheimer’s disease

Position paper
  • Fortunato Battaglia
  • Fabrizio Trinchese
  • Shumin Liu
  • Sean Walter
  • Ralph A. Nixon
  • Ottavio Arancio
Alzheimer’s Therapeutics: Cognitive Enhancement

Abstract

Calpains modulate processes that govern the function and metabolism of proteins key to the pathogenesis of Alzheimer’s disease, including tau and amyloid precursor protein. Because activation of the calpain system might contribute to the impairment of synaptic transmission in Alzheimer’s disease, we are currently testing the hypotheses that a treatment with calpain inhibitors might restore normal cognition and synaptic transmission in a transgenic model of Alzheimer’s disease, the APP (K670N:M671L)/PS1(M146L) mouse. Findings derived from these studies will provide a novel approach to cognitive enhancement in Alzheimer’s disease.

Index Entries

Alzheimer’s disease calpain transgenic models hippocampus amyloid precursor protein presenilin 1 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Bliss T. V. and Collingridge G. L. (1993) A synaptic model of memory: long-term potentiation in the hippocampus. Nature 361, 31–39.PubMedCrossRefGoogle Scholar
  2. Di Rosa G., Odrljin T., Nixon R. A., et al. (2002) Calpain inhibitors: a treatment for Alzheimer’s disease. J. Mol. Neurosci. 19, 135–141.PubMedCrossRefGoogle Scholar
  3. Duff K., Eckman C., Zehr C., et al. (1996) Increased amyloid-beta42(43) in brains of mice expressing mutant presenilin 1. Nature 383, 710–713.CrossRefGoogle Scholar
  4. Grynspan F., Griffin W. R., et al. (1997) Active site-directed antibodies identify calpain II as an early-appearing and pervasive component of neurofibrillary pathology in Alzheimer’s disease. Brain Res. 763, 145–158.PubMedCrossRefGoogle Scholar
  5. Holcomb L., Gordon M. N., McGowan E., et al. (1998) Accelerated Alzheimer-type phenotype in transgenic mice carrying both mutant amyloid precursor protein and presenilin 1 transgenes. Nat. Med. 4, 97–100.PubMedCrossRefGoogle Scholar
  6. Hsiao K., Chapman P., Nilsen S., et al. (1996) Correlative memory deficits, Abeta elevation, and amyloid plaques in transgenic mice. Science 274, 99–102.CrossRefGoogle Scholar
  7. Masliah E. and Terry R. D. (1993) Role of synaptic pathology in the mechanisms of dementia in Alzheimer’s disease. Clin. Neurosci. 1, 192–198.Google Scholar
  8. Morgan D., Diamond D. M., Gottschall P. E., et al, (2000) A beta peptide vaccination prevents memory loss in an animal model of Alzheimer’s disease. Nature 408, 982–985.PubMedCrossRefGoogle Scholar
  9. Nixon R. A., Saito K. I., Grynspan F., et al. (1994) Calcium-activated neutral proteinase (calpain) system in aging and Alzheimer’s disease. Ann NY Acad Sci 747, 77–91.PubMedCrossRefGoogle Scholar
  10. Perlmutter L. S., Siman R., Gall C., et al. (1998) The ultrastructural localization of calcium-activated protease “calpain” in rat brain. Synapse 2, 79–38.CrossRefGoogle Scholar
  11. Saito K., Elce J. S., Hamos J. E., et al. (1993) Widespread activation of calcium-activated neutral proteinase (calpain) in the brain in Alzheimer disease: a potential molecular basis for neuronal degeneration. Proc. Natl. Acad. Sci. USA 90, 2628–2632.PubMedCrossRefGoogle Scholar
  12. Sant Angelo A., Trinchese F., and Arancio O. (2003) Usefulness of behavioural and electrophysiological studies in transgenic models of Alzheiner’s disease. Neurochem. Res. 28, 1009–1015.CrossRefGoogle Scholar
  13. Siman R., Baudry M., and Lynch G. (1984) Brain fodrin: substrate for calpain I, an endogenous calcium activated protease. Proc. Natl. Acad. Sci. USA 81, 3572–3576.PubMedCrossRefGoogle Scholar
  14. Vitolo O. V., Sant’ Angelo A., Costanzo V., et al. (2002) Amyloid beta-peptide inhibition of the PKA/CREB pathway and long-term potentiation: reversibility by drugs that enhance cAMP signaling. Proc. Natl. Acad. Sci. USA 99, 13,217–13,221.CrossRefGoogle Scholar
  15. Wang K. K. (2000) Calpain and caspase: can you tell the difference? Trends Neurosci. 23, 20–26.PubMedCrossRefGoogle Scholar
  16. Wang K. K. W. and Yuen P.-W. (1999) In: Calpain. Pharmacology and Toxicology of Calcium-Dependent Protease (Wang K. K. W. and Yuen P.-W., eds.), Taylor and Francis, Philadelphia, PA, 1999.Google Scholar
  17. Yoshi N., Ohgami T., Yamaguchi H., et al. (1999) Neuroprotective effects of a novel orally active reversible calpain inhibitor BDA-410. Soc. Neurosci. Abstr. 25, 136.8.Google Scholar

Copyright information

© Humana Press Inc 2003

Authors and Affiliations

  • Fortunato Battaglia
    • 1
  • Fabrizio Trinchese
    • 1
  • Shumin Liu
    • 1
  • Sean Walter
    • 1
  • Ralph A. Nixon
    • 1
  • Ottavio Arancio
    • 1
  1. 1.Department of Psychiatry, Nathan Kline Institute for Psychiatric ResearchNYU School of MedicineOrangeburg

Personalised recommendations