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Published on: November 14, 2020
Brain Aggregates: An Effective In Vitro Cell Culture System Modeling Neurodegenerative Diseases
Misol Ahn1, Franck Kalume2, Rose Pitstick2
1From the Department of Pathology (MA, AO, SJD) and Institute for Neurodegenerative Diseases (MA, SJD), University of California San Francisco, California; Department of Pharmacology, University of Washington, Seattle, Washington (FK); and McLaughlin Research Institute, Great Falls, Montana (RP, GC). mahn@ind.ucsf.edu.
Abstract:
Drug discovery for neurodegenerative diseases is particularly challenging because of the discrepancies in drug effects between in vitro and in vivo studies. These discrepancies occur in part because current cell culture systems used for drug screening have many limitations. First, few cell culture systems accurately model human aging or neurodegenerative diseases. Second, drug efficacy may differ between dividing and stationary cells, the latter resembling nondividing neurons in the CNS. Brain aggregates (BrnAggs) derived from embryonic day 15 gestation mouse embryos may represent neuropathogenic processes in prion disease and reflect in vivo drug efficacy. Here, we report a new method for the production of BrnAggs suitable for drug screening and suggest that BrnAggs can model additional neurological diseases such as tauopathies. We also report a functional assay with BrnAggs by measuring electrophysiological activities. Our data suggest that BrnAggs could serve as an effective in vitro cell culture system for drug discovery for neurodegenerative diseases.
Insights
Developing new drugs for neurodegenerative diseases is difficult. Brain aggregates (BrnAggs) offer a promising in vitro model that better reflects in vivo drug efficacy for conditions like prion disease and tauopathies.
Area of Science:
- Neuroscience
- Drug Discovery
- Cell Biology
Background:
- Drug discovery for neurodegenerative diseases faces challenges due to discrepancies between in vitro and in vivo study results.
- Existing cell culture models have limitations in accurately simulating human aging and neurodegenerative conditions.
- Differences in drug efficacy between dividing and non-dividing cells, like those in the central nervous system (CNS), complicate drug screening.
Purpose of the Study:
- To introduce a novel method for generating brain aggregates (BrnAggs) for drug screening.
- To explore the potential of BrnAggs in modeling various neurological diseases beyond prion disease, including tauopathies.
- To establish a functional assay for BrnAggs using electrophysiological measurements.
Main Methods:
- Generation of brain aggregates (BrnAggs) from embryonic day 15 mouse embryos.
- Development of a drug screening platform utilizing BrnAggs.
- Implementation of electrophysiological assays to measure functional activity in BrnAggs.
Main Results:
- BrnAggs derived from mouse embryos show potential in modeling neuropathogenic processes, particularly in prion disease.
- The developed BrnAggs system demonstrated the ability to reflect in vivo drug efficacy.
- Electrophysiological activity measurements confirmed the functional capacity of BrnAggs.
Conclusions:
- Brain aggregates (BrnAggs) represent a viable in vitro model for studying neurodegenerative diseases.
- This novel BrnAggs system can potentially improve the accuracy and efficiency of drug discovery for neurological disorders.
- BrnAggs offer a promising platform for future research into conditions like prion disease and tauopathies.
