Dihydropyridine Derivatives Modulate Heat Shock Responses and have a Neuroprotective Effect in a Transgenic Mouse Model of Alzheimer's Disease

Ágnes Kasza, Ákos Hunya, Zsuzsa Frank, Ferenc Fülöp, Zsolt Török, Gábor Balogh, Miklós Sántha, Árpád Bálind, Sándor Bernáth, Katie L.I.M. Blundell, Chrisostomos Prodromou, Ibolya Horváth, Hans Joachim Zeiler, Philip L. Hooper, László Vigh, Botond Penke, Jose Abisambra

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

Heat shock proteins (Hsps) have chaperone activity and play a pivotal role in the homeostasis of proteins by preventing misfolding, by clearing aggregated and damaged proteins from cells, and by maintaining proteins in an active state. Alzheimer's disease (AD) is thought to be caused by amyloid-β peptide that triggers tau hyperphosphorylation, which is neurotoxic. Although proteostasis capacity declines with age and facilitates the manifestation of neurodegenerative diseases such as AD, the upregulation of chaperones improves prognosis. Our research goal is to identify potent Hsp co-inducers that enhance protein homeostasis for the treatment of AD, especially 1,4-dihydropyridine derivatives optimized for their ability to modulate cellular stress responses. Based on favorable toxicological data and Hsp co-inducing activity, LA1011 was selected for the in vivo analysis of its neuroprotective effect in the APPxPS1 mouse model of AD. Here, we report that 6 months of LA1011 administration effectively improved the spatial learning and memory functions in wild type mice and eliminated neurodegeneration in double mutant mice. Furthermore, Hsp co-inducer therapy preserves the number of neurons, increases dendritic spine density, and reduces tau pathology and amyloid plaque formation in transgenic AD mice. In conclusion, the Hsp co-inducer LA1011 is neuroprotective and therefore is a potential pharmaceutical candidate for the therapy of neurodegenerative diseases, particularly AD.

Original languageEnglish
Pages (from-to)557-571
Number of pages15
JournalJournal of Alzheimer's Disease
Volume53
Issue number2
DOIs
Publication statusPublished - 2016

Keywords

  • Alzheimer's disease
  • Dihydropyridines
  • Heat-shock proteins
  • Hsp co-induction
  • Neuroprotection

ASJC Scopus subject areas

  • Neuroscience(all)
  • Clinical Psychology
  • Geriatrics and Gerontology
  • Psychiatry and Mental health

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    Kasza, Á., Hunya, Á., Frank, Z., Fülöp, F., Török, Z., Balogh, G., Sántha, M., Bálind, Á., Bernáth, S., Blundell, K. L. I. M., Prodromou, C., Horváth, I., Zeiler, H. J., Hooper, P. L., Vigh, L., Penke, B., & Abisambra, J. (2016). Dihydropyridine Derivatives Modulate Heat Shock Responses and have a Neuroprotective Effect in a Transgenic Mouse Model of Alzheimer's Disease. Journal of Alzheimer's Disease, 53(2), 557-571. https://doi.org/10.3233/JAD-150860