Custom Animal Models of Neurodegeneration for Investigation of Potential Therapeutics

Neurodegenerative diseases have a multitude of factors contributing to their pathogenesis, such as tau accumulation, amyloid-β deposition, and altered network oscillations. Synaptic and neuronal loss are also typical of many of neurodegenerative diseases, including frontotemporal dementia and Alzheimer’s Disease (AD). Recent publications have used multiple mouse models of neurodegeneration to explore potential therapeutics for those living with a variety of neurogenerative diseases​.

Potential Non-Invasive Therapeutics Towards Neuroprotection

Researchers previously reported that inducing gamma oscillations with a non-invasive light flicker (gamma entrainment using sensory stimulus, or GENUS) impacts pathology in the visual cortex of multiple mouse models and also demonstrated reduced amyloid plaques and phosphorylated tau¹. In this publication, they demonstrate that GENUS can entrain gamma oscillations in the visual cortex, hippocampus, and prefrontal cortex in Tau P301S and CK-p25 mouse models of neurodegeneration. The Tau P301S and CK-p25 mice subjected to chronic, daily GENUS from the early phases of neurodegeneration show a preservation of neuronal and synaptic density across multiple brain areas and modified cognitive performance. The associated transcriptomic and phosphoproteomic data suggest that continuing GENUS shifts neurons to a less degenerative state, improving synaptic function, enhancing neuroprotective factors, reducing DNA damage in neurons, and reducing the microglial inflammatory response.

Multi-Sensory Gamma Stimulation Provides a Range of Effects

More recent studies designed auditory tone stimulation that drove gamma frequency neural activity in hippocampal CA1 and auditory cortex (AC) - inducing changes in microglia, astrocytes, and vasculature². One week of auditory GENUS was implemented in 5XFAD mice – improving spatial and recognition memory and reduced amyloid in AC and hippocampus. Auditory GENUS also decreased phosphorylated tau in the P301S tauopathy mouse model.

Combined auditory and visual (or multi-sensory) GENUS produced microglial-clustering responses and decreased amyloid in medial prefrontal cortex – which was not demonstrated with the individually- administered sensory stimuli. Whole brain analysis using SHIELD revealed widespread reduction of amyloid plaques throughout the neocortex after multi-sensory GENUS. The variety of effects demonstrated through multiple sensory modalities of GENUS make an effective case for this as a potential therapeutic for the cognitive effects of these diseases.

Custom Mouse Models for the Acceleration of Neurodegenerative Research

While the P301S, CK-p25, and 5XFAD mouse models have provided a basis for the referenced studies of potential non-invasive therapeutics for neurodegenerative diseases - the use of custom mouse models could provide much more clarity to these disease states by more accurately representing the human system(s) of significance for each study. This is especially critical for the broader range of invasive therapeutics; establishing an effective animal model for a particular study can provide significant savings (time & budget) over the long-term by quickly providing in vivo proof of concept & feasibility data.

Cyagen’s proprietary TurboKnockout^® service can provide you with conditional knockout, reporter knockin and humanization mouse models as fast as 6-8 months – customized to represent your targets of interest. TurboKnockout^® provides several advantages over CRISPR-based strategies, including: no off-target effect, guaranteed germline transmission, no mosaicism, and no size limitations for your floxed region. With our combined capabilities, we can help create nearly any genetic variant that you are seeking - with the best guarantee in the industry.

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References

1. Adaikkan, C., Middleton, S. J., Marco, A., Pao, P., Mathys, H., Kim, D. N., . . . Tsai, L. (2019). Gamma Entrainment Binds Higher-Order Brain Regions and Offers Neuroprotection. Neuron,102(5). doi:10.1016/j.neuron.2019.04.011.
2. Martorell, A. J., Paulson, A. L., Suk, H., Abdurrob, F., Drummond, G. T., Guan, W., . . . Tsai, L. (2019). Multi-sensory Gamma Stimulation Ameliorates Alzheimer’s-Associated Pathology and Improves Cognition [Abstract]. Cell,177(2). doi:10.1016/j.cell.2019.02.014.