Hi Alejandro,
Would this be for use in adult humans or is it just meant to edit embryos? There is a problem of delivery of sgRNAs to neurons it's not feasible with the BBB(blood brain barrier). Of course you can access the brain other ways more intrusively. Amyloid beta has been theorized to be able to mitigate excessive calcium levels which are toxic to neurons. Of note, current trials focus on decreasing amyloid beta production such as the use of LY-450139, a gamma-secretase inhibitor. Perhaps Inhibition of GSK3 whilst amyloid beta levels are high via administration of Hyluraonate FGL (modified FG loop peptide) would result in neurogenesis, increased AMPA receptor density, increased dendritic arborization and synapse formation leading to remodeling and repair of lost cognitive function in the diseased brain. Interestingly according to Kim et al. (2019) "in vivo administration of FGL enhanced social and spatial memory retention in rats. FGL prevented cognitive impairment by inhibiting neuronal death and degeneration in an animal model of Alzheimer's disease." Since high amyloid beta supresses extrinsic apoptosis, risk of damage could be mitigated with doses as low as 1mg/day. This may be effective since HA-FGL is 34 times more potent than standard FGL. Additionally HA-FGL is massively angiogenic, there is a keen possibility that it could actually repair damage to the blood brain barrier which is a phenotype associated with APOE4. Personally I am not sure if this would lead to repair of injured pericytes of the BBB (blood brain barrier), but this is where more research is needed. Thus, repairing the damaged caused by APOE4 to the BBB that is a predictive factor for cognitive decline would surely be beneficial right? It then is not puzzling to me then that APOE4 carriers have developed abnormal brain glucose uptake as detected by in vivo positron emission tomography (PET) performed by imaging by Fleisher et al., (2013). Additionally we should look into inhibition of BBB-degrading cyclophilin A-matrix metalloproteinase-9 pathway in the brain. If we look downstream of the cyclophilin A-matrix metalloproteinase-9 pathway, inhibition of NfKB can be achieved via cucurmin. Histone deacetylation associated epigenetic changes are also pathologically related to AD. It has been shown that +NAD (NMN precursor) levels decline with age and lead to less sirtuin gene activation also implicated in epigenetic aging. So supplementation with precursor NMN (nicotinamide adenine mononucleotide) could slow these epigenetic changes. According to Kawahara et al., (2009) "Central actions of SIRT1 are neuroprotective, and there is some evidence that SIRT1 or SIRT6 induction limited to the brain can extend lifespan in mammals, through suppressing metabolic actions of NF-KB in the hypothalamus (SIRT6) and exerting a general neuroprotective effect (SIRT1)." What do you think?
One more thing to consider is that early intervention in transgenic rats with rapamycin might have a protective effect on brain physiological functions and potentially prevent AD for APOE4 carriers according to (Lin et al., 2020). An excerpt from Lin et al., (2020) shows promise here "restore brain glucose uptake, CBF and blood-brain barrier (BBB) integrity in the young APOE4 transgenic mice; the preserved vascular and metabolic functions were associated with amelioration of incipient learning deficits of the APOE4 transgenic mice."
References
Lin, A.-L., Parikh, I., Yanckello, L. M., White, R. S., Hartz, A. M. S., Taylor, C. E., McCulloch, S. D., Thalman, S. W., Xia, M., McCarty, K., Ubele, M., Head, E., Hyder, F., & Sanganahalli, B. G. (2020). APOE genotype-dependent pharmacogenetic responses to rapamycin for preventing Alzheimer’s disease. Neurobiology of Disease, 139. https://doi-org.ezpr...nbd.2020.104834
Fleisher, A. S., Chen, K., Liu, X., Ayutyanont, N., Roontiva, A., Thiyyagura, P., Protas, H., Joshi, A. D., Sabbagh, M., Sadowsky, C. H., Sperling, R. A., Clark, C. M., Mintun, M. A., Pontecorvo, M. J., Coleman, R. E., Doraiswamy, P. M., Johnson, K. A., Carpenter, A. P., Skovronsky, D. M., & Reiman, E. M. (2013). Apolipoprotein E ε4 and age effects on florbetapir positron emission tomography in healthy aging and Alzheimer disease. Neurobiology of Aging, 34(1), 1–12. https://doi-org.ezpr...ing.2012.04.017
Kawahara, T. L. A., Michishita, E., Adler, A. S., Damian, M., Berber, E., Lin, M., McCord, R. A., Ongaigui, K. C. L., Boxer, L. D., Chang, H. Y., & Chua, K. F. (2009). SIRT6 links histone H3 lysine 9 deacetylation to NF-kappaB-dependent gene expression and organismal life span. Cell, 136(1), 62–74. https://doi-org.ezpr...ell.2008.10.052
Lin, A.-L., Parikh, I., Yanckello, L. M., White, R. S., Hartz, A. M. S., Taylor, C. E., McCulloch, S. D., Thalman, S. W., Xia, M., McCarty, K., Ubele, M., Head, E., Hyder, F., & Sanganahalli, B. G. (2020). APOE genotype-dependent pharmacogenetic responses to rapamycin for preventing Alzheimer’s disease. Neurobiology of Disease, 139. https://doi-org.ezpr...nbd.2020.104834
Kim, Y. S., Sung, D. K., Kim, H., Kong, W. H., Kim, Y. E., & Hahn, S. K. (2019). Nose-to-brain delivery of hyaluronate – FG loop peptide conjugate for non-invasive hypoxic-ischemic encephalopathy therapy. Journal of Controlled Release, 307, 76–89. https://doi-org.ezpr...rel.2019.06.021
Wątroba, M., Dudek, I., Skoda, M., Stangret, A., Rzodkiewicz, P., & Szukiewicz, D. (2017). Sirtuins, epigenetics and longevity. Ageing Research Reviews, 40, 11–19. https://doi-org.ezpr...arr.2017.08.001
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