Abstract
Organotypic slice cultures of brain or spinal cord have been a longstanding tool in neuroscience research but their utility for understanding Alzheimer’s disease (AD) and other neurodegenerative proteinopathies has only recently begun to be evaluated. Organotypic brain slice cultures (BSCs) represent a physiologically relevant three-dimensional model of the brain. BSCs support all the central nervous system (CNS) cell types and can be produced from brain areas involved in neurodegenerative disease. BSCs can be used to better understand the induction and significance of proteinopathies underlying the development and progression of AD and other neurodegenerative disorders, and in the future may serve as bridging technologies between cell culture and in vivo experiments for the development and evaluation of novel therapeutic targets and strategies. We review the initial development and general use of BSCs in neuroscience research and highlight the advantages of these cultures as an ex vivo model. Subsequently we focus on i) BSC-based modeling of AD and other neurodegenerative proteinopathies ii) use of BSCs to understand mechanisms underlying these diseases and iii) how BSCs can serve as tools to screen for suitable therapeutics prior to in vivo investigations. Finally, we will examine i) open questions regarding the use of such cultures and ii) how emerging technologies such as recombinant adeno-associated viruses (rAAV) may be combined with these models to advance translational research relevant to neurodegenerative disorders.
Highlights
The cellular and molecular complexity of the brain and spinal cord has presented challenges for ex vivo studies of the central nervous system (CNS)
We describe i) recent advances from our laboratory with respect to using recombinant adeno-associated viral vectors to transduce and model select neurodegenerative pathologies in these cultures and ii) discuss how these Organotypic brain slice culture (BSC) might be used in the future to accelerate both our understanding of CNS diseases and as technology accelerators to identify and validate novel therapeutic strategies
We have shown that Recombinant adeno-associated virus (rAAV)-mediated gene delivery enables the transduction of genes of interest to non-transgenic BSCs to induce abundant Alzheimer’s disease (AD) or Parkinson’s disease (PD) inclusion pathology [29]
Summary
The cellular and molecular complexity of the brain and spinal cord has presented challenges for ex vivo studies of the central nervous system (CNS). Earlier models to study Aβ relied on the addition of exogenous Aβ to induce AD-relevant changes to cultures of the hippocampus or cortex [42] with more recent BSC models prepared from transgenic mice expressing familial mutations in amyloid precursor protein or the presenilins [13, 38].
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