Abstract
Alzheimer's disease, the most common cause of dementia, is a progressive neurodegenerative disorder characterised by amyloid-beta deposits in extracellular plaques, intracellular neurofibrillary tangles of aggregated tau, synaptic dysfunction and neuronal death. Transgenic rodent models to study Alzheimer's mimic features of human disease such as age-dependent accumulation of abnormal beta-amyloid and tau, synaptic dysfunction, cognitive deficits and neurodegeneration. These models have proven vital for improving our understanding of the molecular mechanisms underlying AD and for identifying promising therapeutic approaches. However,modelling neurodegenerative disease in animals commonly involves aging animals until they develop harmful phenotypes, often coupled with invasive procedures. We have developed a novel organotypic brain slice culture model to study Alzheimer's disease using 3xTg-AD mice which brings the potential of substantially reducing the number of rodents used in dementia research from an estimated 20,000 per year. Using a McIllwain tissue chopper, we obtain 36 x 350 micron slices from each P8-P9 mouse pup for culture between 2 weeks and 6 months on semi-permeable 0.4 micron pore membranes, considerably reducing the numbers of animals required to investigate multiple stages of disease. This tractable model also allows the opportunity to modulate multiple pathways in tissues from a single animal. We believe that this model will most benefit dementia researchers in the academic and drug discovery sectors. We validated the slice culture model against aged mice, showing that the molecular phenotype closely mimics that displayed in vivo, albeit in an accelerated timescale. We showed beneficial outcomes following treatment of slices with agents previously shown to have therapeutic effects in vivo, and we also identified new mechanisms of action of other compounds. Thus, organotypic brain slice cultures from transgenic mouse models expressing Alzheimer's disease-related genes may provide a valid and sensitive replacement for in vivo studies that do not involve behavioural analysis.
Highlights
Alzheimer’s disease (AD), the most common cause of dementia, currently affects around 35 million people worldwide and carries huge societal and economical costs
We examined abnormalities in β-amyloid and tau that accumulate in AD brain
We found that 3xTg-AD slice cultures show an accelerated development of highly phosphorylated and oligomeric/64kDa tau species, some of which redistributed to synaptic compartments by 28 days in vitro (DIV)
Summary
Alzheimer’s disease (AD), the most common cause of dementia, currently affects around 35 million people worldwide and carries huge societal and economical costs. The only available treatments for AD target the symptoms of disease, but not disease course. Intensive research efforts are ongoing to better understand the biological causes of disease so that effective disease-modifying therapies can be developed. Perhaps the most accepted models for AD research are transgenic rodents that express wild-type or mutant human AD-associated genes and recapitulate key molecular phenotypes of AD. Mice are generally one of the best accepted animal models in neuroscience research since there is significant homology between the human and mouse genome, mice have a relatively short life span, well-defined genetic backgrounds, are amenable to further genetic manipulations, enable assessment of changes in behaviour, cognition, brain biochemistry and physiology during disease progression, and a battery of wellcharacterised tasks are available to study behaviour and cognition[1]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
