Alzheimers Disease

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.  Although I have not researched this topic before I have found a few interesting details. 

Amyloid beta (Aβ) has been theorized to be able to mitigate excessive calcium levels which are toxic to neurons but Aβ has been shown to be the cause of cerebral blood flow restriction as in (Fig 3).  Of note, current trials focus on decreasing Aβ production such as the use of LY-450139, a gamma-secretase inhibitor.  Perhaps Inhibition of GSK3 whilst Aβ  levels are high via administration of HA-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. HA-FGL prevented cognitive impairment by inhibiting neuronal death and degeneration in an animal model of Alzheimer's disease." Since high Aβ limits extrinsic apoptosis in FGL treated rats, risk of damage could be mitigated with doses as low as 1mg/day in human trials.  This may be effective since HA-FGL is 34 times more potent than standard FGL(FG loop peptide a neural cell adhesion molecule-derived peptide).  Additionally HA-FGL is extremely angiogenic, there is a keen possibility that it could actually repair damage to the blood brain barrier which is a phenotype associated with APOE4. FGL loop peptide has also been shown to decrease damage to CA1 pyramidal cells that were injected with Aβ, potentially through inactivation of GSK3B which is overactive in AD pathologies (Corbet et al., 2013).  

Personally I am not sure if this would lead to repair of injured pericytes we see in (Fig. 1) of the BBB (blood brain barrier), but this is where more research is needed.  Looking at (Fig 2.) research by Nortey et al. (2019) reveals mechanisms of pericyte damage.   So we need to  repair the damage caused by APOE4 to the BBB which 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 upstream of the cyclophilin A-matrix metalloproteinase-9 pathway, inhibition of Nf-KB can be achieved via cucurmin as in (Fig 4) . 

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 " rapamycin was able to 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."

Taken together it looks as if we have some interesting treatments for APOE4 which could be a stop gap until scientists figure out how to perform global genetic engineering in the human brain without detrimental effects.  It's clear that once the damage is done the benefits of APOE4 gene therapy are diminutive without other therapeutic intervention.  

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Fig 1. Blood brain barrier showing pericytes.   Note: Adapted from Zhu, Y., Liu, C., & Pang, Z. (2019). Dendrimer-Based Drug Delivery Systems for Brain Targeting. Biomolecules (2218-273X), 9(12), 790. https://doi-org.ezproxy.umuc.edu/10.3390/biom9120790

Fig 2. Pericyte mediated blood flow restriction. Note: Adapted from Nortley, R., Korte, N., Izquierdo, P., Hirunpattarasilp, C., Mishra, A., Jaunmuktane, Z., Kyrargyri, V., Pfeiffer, T., Khennouf, L., Madry, C., Gong, H., Richard-Loendt, A., Huang, W., Saito, T., Saido, T. C., Brandner, S., Sethi, H., & Attwell, D. (2019). Amyloid β oligomers constrict human capillaries in Alzheimer’s disease via signaling to pericytes. Science (New York, N.Y.), 365(6450). https://doi-org.ezproxy.umuc.edu/10.1126/science.aav9518

Fig 3  Amyloid beta causes capillary restriction and may have a positive feedback loop.  Note: Adapted from Nortley, R., Korte, N., Izquierdo, P., Hirunpattarasilp, C., Mishra, A., Jaunmuktane, Z., Kyrargyri, V., Pfeiffer, T., Khennouf, L., Madry, C., Gong, H., Richard-Loendt, A., Huang, W., Saito, T., Saido, T. C., Brandner, S., Sethi, H., & Attwell, D. (2019). Amyloid β oligomers constrict human capillaries in Alzheimer’s disease via signaling to pericytes. Science (New York, N.Y.), 365(6450). https://doi-org.ezproxy.umuc.edu/10.1126/science.aav9518

Fig 4.  Cucurmin inhibition of Nf-KB. 

References

Corbett, N. J., Gabbott, P. L., Klementiev, B., Davies, H. A., Colyer, F. M., Novikova, T., & Stewart, M. G. (2013). Amyloid-Beta Induced CA1 Pyramidal Cell Loss in Young Adult Rats Is Alleviated by Systemic Treatment with FGL, a Neural Cell Adhesion Molecule-Derived Mimetic Peptide. PLoS ONE, 8(8), 1–11. https://doi-org.ezproxy.umuc.edu/10.1371/journal.pone.0071479

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.ezproxy.umuc.edu/10.1016/j.neurobiolaging.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.ezproxy.umuc.edu/10.1016/j.cell.2008.10.052

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.ezproxy.umuc.edu/10.1016/j.jconrel.2019.06.021

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.ezproxy.umuc.edu/10.1016/j.nbd.2020.104834

Nortley, R., Korte, N., Izquierdo, P., Hirunpattarasilp, C., Mishra, A., Jaunmuktane, Z., Kyrargyri, V., Pfeiffer, T., Khennouf, L., Madry, C., Gong, H., Richard-Loendt, A., Huang, W., Saito, T., Saido, T. C., Brandner, S., Sethi, H., & Attwell, D. (2019). Amyloid β oligomers constrict human capillaries in Alzheimer’s disease via signaling to pericytes. Science (New York, N.Y.), 365(6450). https://doi-org.ezproxy.umuc.edu/10.1126/science.aav9518

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.ezproxy.umuc.edu/10.1016/j.arr.2017.08.001

Zhu, Y., Liu, C., & Pang, Z. (2019). Dendrimer-Based Drug Delivery Systems for Brain Targeting. Biomolecules (2218-273X), 9(12), 790. https://doi-org.ezproxy.umuc.edu/10.3390/biom9120790