CRISPR-Cas9: A Promising Tool in Developing Alzheimer’s Disease Treatment

Haoyi Yang

doi:10.54097/3c0tq464

Authors

Haoyi Yang

DOI:

https://doi.org/10.54097/3c0tq464

Keywords:

Alzheimer’s disease, beta-amyloid, CRISPR-Cas9, gene therapy

Abstract

Alzheimer’s disease (AD) impacts millions of people worldwide, causing cognitive impairment that can get more and more severe as the patients age. Such a disease can also severely impact patients’ lives in the late stage. AD is a sporadic and familial disease. Beta-amyloid (Aβ) and hyperphosphorylated tau protein aggregates directly link to AD pathogenesis, leading to synaptic dysfunction and cognitive decline. When amyloid beta precursor protein (APP) has mutations on the genetic level, patients are likely to have familial AD. In addition, the presenilin (PSEN) gene is another target gene for AD research. Unfortunately, the existing therapies are still ineffective as they can only delay AD progression but cannot stop nor reverse it. Recently, CRISPR-Cas9 has emerged as a promising gene-editing tool in AD research. CRISPR-Cas9 is an outstanding tool compared with the first two generations of gene editing techniques, as CRISPR-Cas9 is cheaper and more efficient. It can create desired mutations in precise positions to target gene sequences, thus potentially manipulating the genes related to familial AD. By mitigating the overproduction of Aβ and tau protein aggregates, researchers aim to slow down or halt the disease progression. CRISPR-Cas9 has significant potential in constructing AD models, screening AD pathogenic genes, and developing targeted therapies for AD. Such a technique offers scientists a better understanding of AD pathogenesis and enlightens more efficient genetic therapies. This review systematically illustrates the CRISPR-Cas9 system and further explains its implementation in AD model constructions, pathogenic genes searching, and potential treatment for AD.

Downloads

Download data is not yet available.

References

J. M. Long and D. M. Holtzman, “Alzheimer Disease: An Update on Pathobiology and Treatment Strategies,” Cell, vol. 179, no. 2, pp. 312–339, Oct. 2019.

H. Sasaguri et al., “APP mouse models for Alzheimer’s disease preclinical studies,” EMBO J., vol. 36, no. 17, pp. 2473–2487, Sep. 2017.

D. S. Knopman et al., “Alzheimer disease,” Nat. Rev. Dis. Primer, vol. 7, no. 1, p. 33, May 2021.

F. Jiang and J. A. Doudna, “CRISPR–Cas9 Structures and Mechanisms,” Annu. Rev. Biophys., vol. 46, no. 1, pp. 505–529, May 2017.

D. Rath, L. Amlinger, A. Rath, and M. Lundgren, “The CRISPR-Cas immune system: Biology, mechanisms and applications,” Biochimie, vol. 117, pp. 119–128, Oct. 2015.

D. Gupta et al., “CRISPR-Cas9 system: A new-fangled dawn in gene editing,” Life Sci., vol. 232, p. 116636, Sep. 2019.

A. Bhardwaj and V. Nain, “TALENs—an indispensable tool in the era of CRISPR: a mini review,” J. Genet. Eng. Biotechnol., vol. 19, no. 1, p. 125, Dec. 2021.

D. Carroll, “Genome Engineering With Zinc-Finger Nucleases,” Genetics, vol. 188, no. 4, pp. 773–782, Aug. 2011.

Y. Wang et al., “Upregulation of Thioredoxin-Interacting Protein in Brain of Amyloid-β Protein Precursor/Presenilin 1 Transgenic Mice and Amyloid-β Treated Neuronal Cells,” J. Alzheimers Dis., vol. 72, no. 1, pp. 139–150, Oct. 2019.

M. Ortiz-Virumbrales et al., “CRISPR/Cas9-Correctable mutation-related molecular and physiological phenotypes in iPSC-derived Alzheimer’s PSEN2 N141I neurons,” Acta Neuropathol. Commun., vol. 5, no. 1, p. 77, Dec. 2017.

A. McQuade et al., “Gene expression and functional deficits underlie TREM2-knockout microglia responses in human models of Alzheimer’s disease,” Nat. Commun., vol. 11, no. 1, p. 5370, Oct. 2020.

S. Pavlou et al., “CRISPR-Cas9 genetic screen leads to the discovery of L-Moses, a KAT2B inhibitor that attenuates Tunicamycin-mediated neuronal cell death,” Sci. Rep., vol. 13, no. 1, p. 3934, Mar. 2023.

B. György et al., “CRISPR/Cas9 Mediated Disruption of the Swedish APP Allele as a Therapeutic Approach for Early-Onset Alzheimer’s Disease,” Mol. Ther. - Nucleic Acids, vol. 11, pp. 429–440, Jun. 2018.

L. Lu, X. Yu, Y. Cai, M. Sun, and H. Yang, “Application of CRISPR/Cas9 in Alzheimer’s Disease,” Front. Neurosci., vol. 15, p. 803894, Dec. 2021.

H. Park, Y. Hwang, and J. Kim, “Transcriptional activation with Cas9 activator nanocomplexes rescues Alzheimer’s disease pathology,” Biomaterials, vol. 279, p. 121229, Dec. 2021.

S. Bhardwaj et al., “CRISPR/Cas9 gene editing: New hope for Alzheimer’s disease therapeutics,” J. Adv. Res., vol. 40, pp. 207–221, Sep. 2022.