title: Dihydropyridine Derivatives Modulate Heat Shock Responses and have a Neuroprotective Effect in a Transgenic Mouse Model of Alzheimer's Disease.
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.
authors.affiliation: Department of Medical Chemistry, University of Szeged, Hungary.
authors.forename: Ágnes
authors.initials: Á
authors.lastname: Kasza
authors.affiliation: LipidArt Research and Development Ltd., Szeged, Hungary.
authors.forename: Ákos
authors.initials: Á
authors.lastname: Hunya
authors.affiliation: Department of Medical Chemistry, University of Szeged, Hungary.
authors.forename: Zsuzsa
authors.initials: Z
authors.lastname: Frank
authors.affiliation: Department of Pharmaceutical Chemistry, University of Szeged, Hungary.
authors.forename: Ferenc
authors.initials: F
authors.lastname: Fülöp
authors.affiliation: LipidArt Research and Development Ltd., Szeged, Hungary.|Biological Research Center of HAS, Institute of Biochemistry, Szeged, Hungary.
authors.forename: Zsolt
authors.initials: Z
authors.lastname: Török
authors.affiliation: Biological Research Center of HAS, Institute of Biochemistry, Szeged, Hungary.
authors.forename: Gábor
authors.initials: G
authors.lastname: Balogh
authors.affiliation: Biological Research Center of HAS, Institute of Biochemistry, Szeged, Hungary.
authors.forename: Miklós
authors.initials: M
authors.lastname: Sántha
authors.affiliation: Biological Research Center of HAS, Institute of Biochemistry, Szeged, Hungary.
authors.forename: Árpád
authors.initials: Á
authors.lastname: Bálind
authors.affiliation: FontaMed Consulting Ltd., Telki, Hungary.
authors.forename: Sándor
authors.initials: S
authors.lastname: Bernáth
authors.affiliation: Genome Damage and Stability Centre, University of Sussex, Falmer, Brighton, UK.
authors.forename: Katie L I M
authors.initials: KL
authors.lastname: Blundell
authors.affiliation: Genome Damage and Stability Centre, University of Sussex, Falmer, Brighton, UK.
authors.forename: Chrisostomos
authors.initials: C
authors.lastname: Prodromou
authors.affiliation: Biological Research Center of HAS, Institute of Biochemistry, Szeged, Hungary.
authors.forename: Ibolya
authors.initials: I
authors.lastname: Horváth
authors.affiliation: Creative Therapeutics GmbH, Wuppertal, Nordrhein-Westfalen, Germany.
authors.forename: Hans-Joachim
authors.initials: HJ
authors.lastname: Zeiler
authors.affiliation: Division of Endocrinology, Metabolism and Diabetes, Department of Medicine, University of Colorado Medical School, Anschutz Medical Campus, Aurora, CO, USA.
authors.forename: Philip L
authors.initials: PL
authors.lastname: Hooper
authors.affiliation: Biological Research Center of HAS, Institute of Biochemistry, Szeged, Hungary.
authors.forename: László
authors.initials: L
authors.lastname: Vigh
authors.affiliation: Department of Medical Chemistry, University of Szeged, Hungary.
authors.forename: Botond
authors.initials: B
authors.lastname: Penke
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D045744:Cell Line, Tumor; D049229:Dendritic Spines / Q000473:pathology / Q000648:ultrastructure; D004095:Dihydropyridines / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D006360:Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D009447:Neuroblastoma / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D053764:Presenilin-1 / Q000235:genetics / Q000378:metabolism; D016875:tau Proteins / Q000378:metabolism
chemical_list: D016564:Amyloid beta-Protein Precursor; D004095:Dihydropyridines; D006360:Heat-Shock Proteins; D018696:Neuroprotective Agents; C508853:PSEN1 protein, human; D053764:Presenilin-1; D016875:tau Proteins; C038806:1,4-dihydropyridine
keywords: Alzheimer’s disease; Hsp co-induction; dihydropyridines; heat-shock proteins; neuroprotection