title: In vitro modelling of Alzheimer's disease: degeneration and cell death induced by viral delivery of amyloid and tau.
abstract: With increasing life expectancy, Alzheimer's disease (AD) and other dementias pose an increasing and as yet unresolved health problem. A variety of cellular models of AD has helped to decipher some key aspects of amyloid and tau related degeneration. The initial approach of extracellular applications of synthetic peptides has now been replaced by the introduction of amyloid precursor protein (APP) and tau genes. In the present study adenoviral transductions were exploited for gene delivery into primary rat hippocampal and dorsal root ganglion (DRG) cultures to enable comparative and mechanistic studies at the cellular level and subsequent drug testing. Time lapse experiments revealed a different pattern of cell death: apoptotic-like for APP whereas tau positive cells joined and formed clusters. Mutated human APP or tau expression caused accelerated neuronal damage and cell death (cf. EGFP: -50% for APP at 5 days; -40% for tau at 3 days). This reduction in viability was preceded by decreased excitability, monitored via responses to depolarising KCl-challenges in Ca(2+) imaging experiments. Additionally, both transgenes reduced neurite outgrowth in DRG neurones. Treatment studies confirmed that APP induced-damage can be ameliorated by β- and γ-secretase inhibitors (providing protection to 60-100% of control levels), clioquinol (80%) and lithium (100%); while anti-aggregation treatments were beneficial for tau-induced damage (60-90% recovery towards controls). Interestingly, caffeine was the most promising drug candidate for therapeutic intervention with high efficacy in both APP (77%) and tau-induced models (72% recovery). Overall, these cellular models offer advantages for mechanistic studies and target identification in AD and related disorders.
authors.affiliation: School of Medical Sciences, College of Life Sciences and Medicine, University of Aberdeen, Institute of Medical Sciences, Foresterhill, Aberdeen AB25 2ZD Scotland, UK.
authors.forename: Sandra
authors.initials: S
authors.lastname: Stoppelkamp
authors.forename: Helen S
authors.initials: HS
authors.lastname: Bell
authors.forename: Jon
authors.initials: J
authors.lastname: Palacios-Filardo
authors.forename: Derryck A
authors.initials: DA
authors.lastname: Shewan
authors.forename: Gernot
authors.initials: G
authors.lastname: Riedel
authors.forename: Bettina
authors.initials: B
authors.lastname: Platt
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism; D016923:Cell Death / Q000235:genetics*; D002460:Cell Line; D002478:Cells, Cultured; D003712:Dendrites / Q000378:metabolism / Q000473:pathology; D005727:Ganglia, Spinal / Q000378:metabolism / Q000473:pathology; D005822:Genetic Vectors; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology; D009410:Nerve Degeneration / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014161:Transduction, Genetic / Q000379:methods*; D016875:tau Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D016875:tau Proteins; D002118:Calcium