A recent preprint paper from researchers at Sachi Bio has described how this company’s technology can be used to alleviate brain inflammation in a mouse model.
The problem of tau
Along with the infamous amyloid beta, tau is well-known as a pathological factor in both Alzheimer’s and regular aging [1]. The accumulation of tau with aging causes the chronic overactivation of the brain’s immune system on multiple levels [2], leading to neuroinflammation and making the problem worse [3].
To combat this problem, previous research has focused on targeting the key pathways associated with neuroinflammation, an approach that has seen some success in previous models [4]. However, this sort of approach may also have off-target effects in the brain, inhibiting other enzymes [5]. Additionally, these researchers note that many prospective treatments cannot cross the blood-brain barrier.
These researchers, some of which include Sachi Bio’s founders and employees, believe that this company’s Nanoligomer technology might be able to solve this problem. This is a form of nanotechnology that binds specialized RNA into a gold nanoparticle [6], crosssing the blood-brain barrier, entering cells, and suppressing both the DNA and RNA of the inflammatory factors NF-κB and NLRP3.
Short-term and long-term experiments
In their first experiment, the researchers administered their Nanoligomer to 19-month-old wild-type Black 6 mice, at 150 milligrams per kilogram of body weight. These mice showed reductions in both NF-κB and NLRP3 within 16 hours after administration, and their levels of activated NF-κB were more like those of young mice.
Those results encouraged the researchers to test long-term effects. The researchers administered their nanoparticle at the same dose to both old wild-type mice and to a mouse model of tauopathy. The treatment did not have adverse effects on any of the mice.
Both older wild-type and tauopathic mice performed better on a measurement of novel object recognition, which reflects mental flexibility in mice. An elevated maze test did not yield any statistically significant results, but the trend was towards better performance. Forelimb grip strength was also better in older treated mice. The researchers did not test other metrics of physical performance, such as the rotarod test.
A principal component analysis revealed that a wide variety of inflammatory molecules, which are increased with aging and tauopathy, were reduced by this Nanoligomer treatment in both old mice and the tauopathy model. The overactivation of glial immune cells was also diminished, and an analysis of gene transcription confirmed that immune activity was being reduced. There were also beneficial reductions in inflammation throughout the mice’s bodies, particularly in the liver.
Previous work has found that tauopathy and inflammation are causative of each other [7]; rather than reducing tau, the resulting inflammation makes the condition worse. In the tauopathic mice, treatment with this Nanoligomer drove down the amounts of tau, suggesting that the reduction of neuroinflammation also diminished its cause.
While these researchers report positive results, they note that this is only a limited study, and they wish to undertake a more complex multi-omics analysis in order to better gauge its total effects. Additionally, mouse results may or may not be applicable to human beings. Clinical trials will have to be conducted to determine whether or not this approach reduces inflammatory factors in people and whether or not that translates into clinical benefit.
Literature
[1] Xia, X., Jiang, Q., McDermott, J., & Han, J. D. J. (2018). Aging and Alzheimer’s disease: comparison and associations from molecular to system level. Aging cell, 17(5), e12802.
[2] Heneka, M. T., Kummer, M. P., & Latz, E. (2014). Innate immune activation in neurodegenerative disease. Nature Reviews Immunology, 14(7), 463-477.
[3] Metcalfe, M. J., & Figueiredo‐Pereira, M. E. (2010). Relationship between tau pathology and neuroinflammation in Alzheimer’s disease. Mount Sinai Journal of Medicine: A Journal of Translational and Personalized Medicine, 77(1), 50-58.
[4] Dempsey, C., Araiz, A. R., Bryson, K. J., Finucane, O., Larkin, C., Mills, E. L., … & Lynch, M. A. (2017). Inhibiting the NLRP3 inflammasome with MCC950 promotes non-phlogistic clearance of amyloid-β and cognitive function in APP/PS1 mice. Brain, behavior, and immunity, 61, 306-316.
[5] Kennedy, C. R., Goya Grocin, A., Kovačič, T., Singh, R., Ward, J. A., Shenoy, A. R., & Tate, E. W. (2021). A probe for NLRP3 inflammasome inhibitor MCC950 identifies carbonic anhydrase 2 as a novel target. ACS chemical biology, 16(6), 982-990.
[6] Sharma, S., Borski, C., Hanson, J., Garcia, M. A., Link, C. D., Hoeffer, C., … & Nagpal, P. (2022). Identifying an Optimal Neuroinflammation Treatment Using a Nanoligomer Discovery Engine. ACS Chemical Neuroscience, 13(23), 3247-3256.
[7] Wang, C., Fan, L., Khawaja, R. R., Liu, B., Zhan, L., Kodama, L., … & Gan, L. (2022). Microglial NF-κB drives tau spreading and toxicity in a mouse model of tauopathy. Nature communications, 13(1), 1969.
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