Document Detail

In vitro modelling of Alzheimer's disease: degeneration and cell death induced by viral delivery of amyloid and tau.
MedLine Citation:
PMID:  21295028     Owner:  NLM     Status:  MEDLINE    
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 The initial approach of extracellular applications of synthetic peptides has now been replaced by the introduction of amyloid precursor protein (APP) and tau genes.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.
Sandra Stoppelkamp; Helen S Bell; Jon Palacios-Filardo; Derryck A Shewan; Gernot Riedel; Bettina Platt
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Publication Detail:
Type:  Journal Article     Date:  2011-02-02
Journal Detail:
Title:  Experimental neurology     Volume:  229     ISSN:  1090-2430     ISO Abbreviation:  Exp. Neurol.     Publication Date:  2011 Jun 
Date Detail:
Created Date:  2011-05-23     Completed Date:  2011-08-05     Revised Date:  2012-03-08    
Medline Journal Info:
Nlm Unique ID:  0370712     Medline TA:  Exp Neurol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  226-37     Citation Subset:  IM    
Copyright Information:
Copyright © 2011 Elsevier Inc. All rights reserved.
School of Medical Sciences, College of Life Sciences and Medicine, University of Aberdeen, Institute of Medical Sciences, Foresterhill, Aberdeen AB25 2ZD Scotland, UK.
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MeSH Terms
Adenoviridae / genetics*
Alzheimer Disease / genetics*,  metabolism,  pathology
Amyloid beta-Peptides / genetics*,  metabolism
Blotting, Western
Calcium / metabolism
Cell Death / genetics*
Cell Line
Cells, Cultured
Dendrites / metabolism,  pathology
Ganglia, Spinal / metabolism,  pathology
Genetic Vectors
Hippocampus / metabolism,  pathology
Nerve Degeneration / genetics*,  metabolism,  pathology
Neurons / metabolism,  pathology
Rats, Sprague-Dawley
Transduction, Genetic / methods*
tau Proteins / genetics*,  metabolism
Reg. No./Substance:
0/Amyloid beta-Peptides; 0/tau Proteins; 7440-70-2/Calcium
Comment In:
Exp Neurol. 2012 Feb;233(2):733-9   [PMID:  22119424 ]

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