Journal of Molecular Neuroscience

, Volume 45, Issue 1, pp 22–31

The γ-Secretase Modulator CHF5074 Reduces the Accumulation of Native Hyperphosphorylated Tau in a Transgenic Mouse Model of Alzheimer’s Disease

  • Annamaria Lanzillotta
  • Ilenia Sarnico
  • Marina Benarese
  • Caterina Branca
  • Cristina Baiguera
  • Birgit Hutter-Paier
  • Manfred Windisch
  • PierFranco Spano
  • Bruno Pietro Imbimbo
  • Marina Pizzi
Article

DOI: 10.1007/s12031-010-9482-2

Cite this article as:
Lanzillotta, A., Sarnico, I., Benarese, M. et al. J Mol Neurosci (2011) 45: 22. doi:10.1007/s12031-010-9482-2

Abstract

The relationship between β-amyloid (Aβ) and tau is not fully understood, though it is proposed that in the pathogenesis of Alzheimer’s disease (AD) Aβ accumulation precedes and promotes tau hyperphosphorylation via activation of glycogen synthase kinase-3beta (GSK-3β). Both events contribute to learning and memory impairments. Modulation of γ-secretase activity has proved to reduce the Aβ burden and cognitive deficits in mouse models of AD, but its ability in reducing the tau pathology remains elusive. Chronic treatments with two γ-secretase modulators, ibuprofen and CHF5074, disclosed higher activity of CHF5074 in ameliorating brain plaque deposition and spatial memory deficits in transgenic mice expressing human amyloid precursor protein (hAPP) with Swedish and London mutations (APPSL mice). The aim of our study was to investigate in APPSL mice the effect of the two compounds on the accumulation of native hyperphosphorylated tau as well as on the GSK-3β signaling. CHF5074 was more effective than ibuprofen in reducing tau pathology, though both compounds decreased the GSK-3β level and increased the GSK-3β inhibitory phosphorylation near to the non-Tg values. The inhibition of GSK-3β appeared to be secondary to the reduction of Aβ generation as, differently from LiCl, CHF5074 reproduced its effect in hAPP-overexpressing neuroglioma cells, but not in wild-type primary neurons. Our data show that the novel γ-secretase modulator CHF5074 can fully reverse β-amyloid-associated tau pathology, thus representing a promising therapeutic agent for AD.

Keywords

AlzheimerTauHuman APP transgenic miceIbuprofenCHF5074

Abbreviations

β-Amyloid

AD

Alzheimer’s disease

hAPPSL

Human amyloid precursor protein with Swedish and London mutations

COX

Cyclooxygenase

CHF5074

1-(3′,4′-dichloro-2-fluoro[1,1′-biphenyl]-4-yl)-cyclopropanecarboxylic acid

GAPDH

Glyceraldehydes-3-phosphate dehydrogenase

GSK-3β

Glycogen synthase kinase-3beta

LiCl

Lithium chloride

NFTs

Neurofibrillary tangles

PHF-1

Paired helical filament-1

Ser

Serine

Swe

Swedish mutation

Tg

Transgenic

Thr

Threonine

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Annamaria Lanzillotta
    • 1
  • Ilenia Sarnico
    • 1
  • Marina Benarese
    • 1
  • Caterina Branca
    • 1
  • Cristina Baiguera
    • 1
  • Birgit Hutter-Paier
    • 3
  • Manfred Windisch
    • 3
  • PierFranco Spano
    • 1
    • 2
  • Bruno Pietro Imbimbo
    • 4
  • Marina Pizzi
    • 1
    • 2
    • 5
  1. 1.Division of Pharmacology and Experimental Therapeutics, Department of Biomedical Sciences and Biotechnologies, School of MedicineUniversity of Brescia and Istituto Nazionale di Neuroscienze BresciaBresciaItaly
  2. 2.Istituto Ricovero e Cura a Carattere ScientificoS. Camillo HospitalVeniceItaly
  3. 3.JSW Life Sciences GmbHGrambachAustria
  4. 4.Research and DevelopmentChiesi FarmaceuticiParmaItaly
  5. 5.Division of Pharmacology, Department of Biomedical Sciences and Biotechnologies University of BresciaBresciaItaly