Skip to main content

Advertisement

SpringerLink
Log in

Application of CRISPR/Cas9 System in the Treatment of Alzheimer’s Disease and Neurodegenerative Diseases

  • Reviews
  • Published:
Molecular Neurobiology Aims and scope Submit manuscript

Abstract

Alzheimer’s, Parkinson’s, and Huntington’s are some of the most common neurological disorders, which affect millions of people worldwide. Although there have been many treatments for these diseases, there are still no effective treatments to treat or completely stop these disorders. Perhaps the lack of proper treatment for these diseases can be related to various reasons, but the poor results related to recent clinical research also prompted doctors to look for new treatment approaches. In this regard, various researchers from all over the world have provided many new treatments, one of which is CRISPR/Cas9. Today, the CRISPR/Cas9 system is mostly used for genetic modifications in various species. In addition, by using the abilities available in the CRISPR/Cas9 system, researchers can either remove or modify DNA sequences, which in this way can establish a suitable and useful treatment method for the treatment of genetic diseases that have undergone mutations. We conducted a non-systematic review of articles and study results from various databases, including PubMed, Medline, Web of Science, and Scopus, in recent years. and have investigated new treatment methods in neurodegenerative diseases with a focus on Alzheimer’s disease. Then, in the following sections, the treatment methods were classified into three groups: anti-tau, anti-amyloid, and anti-APOE regimens. Finally, we discussed various applications of the CRISPR/Cas-9 system in Alzheimer’s disease. Today, using CRISPR/Cas-9 technology, scientists create Alzheimer’s disease models that have a more realistic phenotype and reveal the processes of pathogenesis; following the screening of defective genes, they establish treatments for this disease.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

Data Availability

These data were obtained by other papers. If needed, it will be available to reviews and editors.

References

  1. Gitler AD, Dhillon P, Shorter J (2017) Neurodegenerative disease: models, mechanisms, and new hope. Dis Model Mech 10(5):499–502

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Checkoway H, Lundin JI, Kelada SN (2011) Neurodegenerative diseases. IARC Sci Publ 163:407–419

    Google Scholar 

  3. Wilson DM, Cookson MR, Van Den Bosch L, Zetterberg H, Holtzman DM, Dewachter I (2023) Hallmarks of neurodegenerative diseases. Cell. 186(4):693–714

    Article  CAS  PubMed  Google Scholar 

  4. Gan L, Cookson MR, Petrucelli L, La Spada AR (2018) Converging pathways in neurodegeneration, from genetics to mechanisms. Nat Neurosci 21(10):1300–1309

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Kumar A, Sidhu J, Goyal A, Tsao JW (2023) Alzheimer Disease. StatPearls. Treasure Island (FL) ineligible companies. Disclosure: Jaskirat Sidhu declares no relevant financial relationships with ineligible companies. Disclosure: Amandeep Goyal declares no relevant financial relationships with ineligible companies. In: Disclosure: Jack Tsao declares no relevant financial relationships with ineligible companies.: StatPearls Publishing Copyright © 2023. StatPearls Publishing LLC

    Google Scholar 

  6. Silva MVF, Loures CMG, Alves LCV, de Souza LC, Borges KBG, Carvalho MG (2019) Alzheimer’s disease: risk factors and potentially protective measures. J Biomed Sci 26(1):33

    Article  PubMed  PubMed Central  Google Scholar 

  7. DeMaagd G, Philip A (2015) Parkinson's disease and its management: part 1: disease entity, risk factors, pathophysiology, clinical presentation, and diagnosis. P & T : a Peer-Rev J Formula Manag 40(8):504–532

    Google Scholar 

  8. McColgan P, Tabrizi SJ (2018) Huntington's disease: a clinical review. Eur J Neurol 25(1):24–34

    Article  CAS  PubMed  Google Scholar 

  9. Roos RAC (2010) Huntington's disease: a clinical review. Orphanet J Rare Dis 5(1):40

    Article  PubMed  PubMed Central  Google Scholar 

  10. Masrori P, Van Damme P (2020) Amyotrophic lateral sclerosis: a clinical review. Eur J Neurol 27(10):1918–1929

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Hou Y, Dan X, Babbar M, Wei Y, Hasselbalch SG, Croteau DL et al (2019) Ageing as a risk factor for neurodegenerative disease. Nat Rev Neurol 15(10):565–581

    Article  PubMed  Google Scholar 

  12. Cascione M, De Matteis V, Leporatti S, Rinaldi R (2020) The new frontiers in neurodegenerative diseases treatment: liposomal-based strategies. Front Bioeng Biotechnol 8:566767

    Article  PubMed  PubMed Central  Google Scholar 

  13. Lipton SA (2004) Failures and successes of NMDA receptor antagonists: molecular basis for the use of open-channel blockers like memantine in the treatment of acute and chronic neurologic insults. NeuroRX 1(1):101–110

    Article  PubMed  PubMed Central  Google Scholar 

  14. Hallett PJ, Standaert DG (2004) Rationale for and use of NMDA receptor antagonists in Parkinson's disease. Pharmacol Ther 102(2):155–174

    Article  CAS  PubMed  Google Scholar 

  15. Luo D, Reith M, Dutta AK (2020) Chapter 26 - dopamine agonists in treatment of Parkinson's disease: an overview. In: Martin CR, Preedy VR (eds) Diagnosis and Management in Parkinson's Disease. Academic Press, pp. 445–460

    Chapter  Google Scholar 

  16. Armstrong MJ, Okun MS (2020) Diagnosis and treatment of Parkinson disease: a review. Jama 323(6):548–560

    Article  PubMed  Google Scholar 

  17. Caraci F, Santagati M, Caruso G, Cannavò D, Leggio GM, Salomone S et al (2020) New antipsychotic drugs for the treatment of agitation and psychosis in Alzheimer's disease: focus on brexpiprazole and pimavanserin. F1000Res 9. https://doi.org/10.12688/f1000research.22662.1

  18. Song C, Shi J, Zhang P, Zhang Y, Xu J, Zhao L et al (2022) Immunotherapy for Alzheimer's disease: targeting β-amyloid and beyond. Transl Neurodegen 11(1):18

    Article  CAS  Google Scholar 

  19. Sudhakar V, Richardson RM (2019) Gene therapy for neurodegenerative diseases. Neurotherapeutics 16(1):166–175

    Article  CAS  PubMed  Google Scholar 

  20. Lamptey RNL, Chaulagain B, Trivedi R, Gothwal A, Layek B, Singh J (2022) A review of the common neurodegenerative disorders: current therapeutic approaches and the potential role of nanotherapeutics. Int J Mol Sci 23(3):1851

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Afzal SM, Vafa A, Rashid S, Barnwal P, Shahid A, Shree A et al (2021) Protective effect of hesperidin against N, N′-dimethylhydrazine induced oxidative stress, inflammation, and apoptotic response in the colon of Wistar rats. Environ Toxicol 36(4):642–653

    Article  CAS  Google Scholar 

  22. Breijyeh Z, Karaman R (2020) Comprehensive review on Alzheimer’s disease: causes and treatment. Molecules 25(24):5789

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Czapiewski S, Brown-Nyseth V (2016) Syndromes of brain dysfunction presenting with cognitive impairment or behavioral disturbance: delirium, dementia, and mental disorders due to another medical condition. The Med Basis Psychiatr:17–41

  24. Livingston G, Huntley J, Sommerlad A, Ames D, Ballard C, Banerjee S et al (2020) Dementia prevention, intervention, and care: 2020 report of the Lancet Commission. Lancet 396(10248):413–446

    Article  PubMed  PubMed Central  Google Scholar 

  25. Serrano-Pozo A, Frosch MP, Masliah E, Hyman BT (2011) Neuropathological alterations in Alzheimer disease. Cold Spring Harb Perspect Med 1(1):a006189

    Article  PubMed  PubMed Central  Google Scholar 

  26. Khanahmadi M, Farhud DD, Malmir M (2015) Genetic of Alzheimer’s disease: a narrative review article. Iran J Public Health 44(7):892

    PubMed  PubMed Central  Google Scholar 

  27. Wen K-x, Milic J, El-Khodor B, Dhana K, Nano J, Pulido T et al (2016) The role of DNA methylation and histone modifications in neurodegenerative diseases: a systematic review. Plos One 11(12):e0167201

    Article  PubMed  PubMed Central  Google Scholar 

  28. Zhao L, Woody SK, Chhibber A (2015) Estrogen receptor β in Alzheimer’s disease: from mechanisms to therapeutics. Ageing Res Rev 24:178–190

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Hu N, Yu J-T, Tan L, Wang Y-L, Sun L, Tan L (2013) Nutrition and the risk of Alzheimer's disease. Biomed Res Int 2013. https://doi.org/10.1155/2013/524820

  30. Adlard PA, Bush AI (2006) Metals and Alzheimer's disease. J Alzheimers Dis 10(2-3):145–163

    Article  PubMed  Google Scholar 

  31. Baglietto-Vargas D, Shi J, Yaeger DM, Ager R, LaFerla FM (2016) Diabetes and Alzheimer’s disease crosstalk. Neurosci Biobehav Rev 64:272–287

    Article  CAS  PubMed  Google Scholar 

  32. de Toledo Ferraz Alves TC, Ferreira LK, Wajngarten M, Busatto GF (2010) Cardiac disorders as risk factors for Alzheimer's disease. J Alzheimers Dis 20(3):749–763

    Article  PubMed  Google Scholar 

  33. Turner RS, Stubbs T, Davies DA, Albensi BC (2020) Potential new approaches for diagnosis of Alzheimer's disease and related dementias. Front Neurol 11:496

    Article  PubMed  PubMed Central  Google Scholar 

  34. Blennow K, Zetterberg H (2018) Biomarkers for Alzheimer's disease: current status and prospects for the future. J Intern Med 284(6):643–663

    Article  CAS  PubMed  Google Scholar 

  35. Vaz M, Silvestre S (2020) Alzheimer's disease: recent treatment strategies. Eur J Pharmacol 887:173554

    Article  CAS  PubMed  Google Scholar 

  36. Hanafy AS, Schoch S, Lamprecht A (2020) CRISPR/CAS9 delivery potentials in Alzheimer’s disease management: a mini review. Pharmaceutics 12(9):801

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Egan MF, Kost J, Tariot PN, Aisen PS, Cummings JL, Vellas B et al (2018) Randomized trial of verubecestat for mild-to-moderate Alzheimer’s disease. N Engl J Med 378(18):1691–1703

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Egan MF, Kost J, Voss T, Mukai Y, Aisen PS, Cummings JL et al (2019) Randomized trial of verubecestat for prodromal Alzheimer’s disease. N Engl J Med 380(15):1408–1420

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Cummings J, Lee G, Ritter A, Zhong K (2018) Alzheimer's disease drug development pipeline: 2018. Alzheimer's & Dementia 4:195–214

    Article  Google Scholar 

  40. Green RC, Schneider LS, Amato DA, Beelen AP, Wilcock G, Swabb EA et al (2009) Effect of tarenflurbil on cognitive decline and activities of daily living in patients with mild Alzheimer disease: a randomized controlled trial. Jama 302(23):2557–2564

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Coric V, Salloway S, van Dyck CH, Dubois B, Andreasen N, Brody M et al (2015) Targeting prodromal Alzheimer disease with avagacestat: a randomized clinical trial. JAMA Neurol 72(11):1324–1333

    Article  PubMed  Google Scholar 

  42. Sampson EL, Jenagaratnam L, McShane R (2014) Metal protein attenuating compounds for the treatment of Alzheimer's dementia. Cochrane Database Syst Rev 2. https://doi.org/10.1002/14651858.CD005380.pub5

  43. Ritchie CW, Bush AI, Mackinnon A, Macfarlane S, Mastwyk M, MacGregor L et al (2003) Metal-protein attenuation with iodochlorhydroxyquin (clioquinol) targeting Aβ amyloid deposition and toxicity in Alzheimer disease: a pilot phase 2 clinical trial. Arch Neurol 60(12):1685–1691

    Article  PubMed  Google Scholar 

  44. Lannfelt L, Blennow K, Zetterberg H, Batsman S, Ames D, Harrison J et al (2008) Safety, efficacy, and biomarker findings of PBT2 in targeting Aβ as a modifying therapy for Alzheimer's disease: a phase IIa, double-blind, randomised, placebo-controlled trial. The Lancet Neurol 7(9):779–786

    Article  CAS  PubMed  Google Scholar 

  45. Pagano K, Tomaselli S, Molinari H, Ragona L (2020) Natural compounds as inhibitors of Aβ peptide aggregation: chemical requirements and molecular mechanisms. Front Neurosci 14:619667

    Article  PubMed  PubMed Central  Google Scholar 

  46. Mantile F, Prisco A (2020) Vaccination against β-amyloid as a strategy for the prevention of Alzheimer’s disease. Biology 9(12):425

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Pillai R, Uyehara-Lock JH, Bellinger FP (2014) Selenium and selenoprotein function in brain disorders. IUBMB Life 66(4):229–239

    Article  CAS  PubMed  Google Scholar 

  48. Khalil HS, Mitev V, Vlaykova T, Cavicchi L, Zhelev N (2015) Discovery and development of Seliciclib. How systems biology approaches can lead to better drug performance. J Biotechnol 202:40–49

    Article  CAS  PubMed  Google Scholar 

  49. Leggio GM, Catania MV, Puzzo D, Spatuzza M, Pellitteri R, Gulisano W et al (2016) The antineoplastic drug flavopiridol reverses memory impairment induced by amyloid-ß1-42 oligomers in mice. Pharmacol Res 106:10–20

    Article  CAS  PubMed  Google Scholar 

  50. Lovestone S, Boada M, Dubois B, Hüll M, Rinne JO, Huppertz H-J et al (2015) A phase II trial of tideglusib in Alzheimer's disease. J Alzheimers Dis 45(1):75–88

    Article  CAS  PubMed  Google Scholar 

  51. Andrade Nunes M, Araujo Viel T, Sousa BH (2013) Microdose lithium treatment stabilized cognitive impairment in patients with Alzheimer's disease. Curr Alzheimer Res 10(1):104–107

    Google Scholar 

  52. Matsunaga S, Fujishiro H, Takechi H (2019) Efficacy and safety of glycogen synthase kinase 3 inhibitors for Alzheimer’s disease: a systematic review and meta-analysis. J Alzheimers Dis 69(4):1031–1039

    Article  CAS  PubMed  Google Scholar 

  53. Yu T-W, Lane H-Y, Lin C-H (2021) Novel therapeutic approaches for Alzheimer’s disease: an updated review. Int J Mol Sci 22(15):8208

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Wischik CM, Staff RT, Wischik DJ, Bentham P, Murray AD, Storey J et al (2015) Tau aggregation inhibitor therapy: an exploratory phase 2 study in mild or moderate Alzheimer's disease. J Alzheimers Dis 44(2):705–720

    Article  CAS  PubMed  Google Scholar 

  55. Gauthier S, Feldman HH, Schneider LS, Wilcock GK, Frisoni GB, Hardlund JH et al (2016) Efficacy and safety of tau-aggregation inhibitor therapy in patients with mild or moderate Alzheimer's disease: a randomised, controlled, double-blind, parallel-arm, phase 3 trial. Lancet 388(10062):2873–2884

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Cox KH, Pipingas A, Scholey AB (2015) Investigation of the effects of solid lipid curcumin on cognition and mood in a healthy older population. J Psychopharmacol 29(5):642–651

    Article  CAS  PubMed  Google Scholar 

  57. Gozes I (2011) Microtubules (tau) as an emerging therapeutic target: NAP (davunetide). Curr Pharm Des 17(31):3413–3417

    Article  CAS  PubMed  Google Scholar 

  58. Morimoto BH, Fox AW, Stewart AJ, Gold M (2013) Davunetide: a review of safety and efficacy data with a focus on neurodegenerative diseases. Expert Rev Clin Pharmacol 6(5):483–502

    Article  CAS  PubMed  Google Scholar 

  59. Bollag DM, McQueney PA, Zhu J, Hensens O, Koupal L, Liesch J et al (1995) Epothilones, a new class of microtubule-stabilizing agents with a taxol-like mechanism of action. Cancer Res 55(11):2325–2333

    CAS  PubMed  Google Scholar 

  60. Fitzgerald DP, Emerson DL, Qian Y, Anwar T, Liewehr DJ, Steinberg SM et al (2012) TPI-287, a new taxane family member, reduces the brain metastatic colonization of breast cancer cells. Mol Cancer Ther 11(9):1959–1967

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Zumbar CT, Usubalieva A, King PD, Li X, Mifsud CS, Dalton HM et al (2018) The CNS penetrating taxane TPI 287 and the AURKA inhibitor alisertib induce synergistic apoptosis in glioblastoma cells. J Neuro-Oncol 137:481–492

    Article  CAS  Google Scholar 

  62. Gozes I (2011) NAP (davunetide) provides functional and structural neuroprotection. Curr Pharm Des 17(10):1040–1044

    Article  CAS  PubMed  Google Scholar 

  63. Panza F, Solfrizzi V, Seripa D, Imbimbo BP, Lozupone M, Santamato A et al (2016) Tau-based therapeutics for Alzheimer’s disease: active and passive immunotherapy. Immunotherapy 8(9):1119–1134

    Article  CAS  PubMed  Google Scholar 

  64. Novak P, Zilka N, Zilkova M, Kovacech B, Skrabana R, Ondrus M et al (2019) AADvac1, an active immunotherapy for Alzheimer’s disease and non Alzheimer tauopathies: an overview of preclinical and clinical development. J Prev Alzheimers Dis 6:63–69

    CAS  PubMed  Google Scholar 

  65. Theunis C, Crespo-Biel N, Gafner V, Pihlgren M, López-Deber MP, Reis P et al (2013) Efficacy and safety of a liposome-based vaccine against protein Tau, assessed in tau. P301L mice that model tauopathy. PloS one 8(8):e72301

    Article  PubMed  PubMed Central  Google Scholar 

  66. Hoskin JL, Sabbagh MN, Al-Hasan Y, Decourt B (2019) Tau immunotherapies for Alzheimer’s disease. Expert Opin Investig Drugs 28(6):545–554

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Qureshi IA, Tirucherai G, Ahlijanian MK, Kolaitis G, Bechtold C, Grundman M (2018) A randomized, single ascending dose study of intravenous BIIB092 in healthy participants. Alzheimer's & Dementia 4:746–755

    Article  Google Scholar 

  68. Cao J, Hou J, Ping J, Cai D (2018) Advances in developing novel therapeutic strategies for Alzheimer’s disease. Mol Neurodegener 13:1–20

    Article  Google Scholar 

  69. Boehm-Cagan A, Bar R, Liraz O, Bielicki JK, Johansson JO, Michaelson DM (2016) ABCA1 agonist reverses the ApoE4-driven cognitive and brain pathologies. J Alzheimers Dis 54(3):1219–1233

    Article  CAS  PubMed  Google Scholar 

  70. Santos DB, Peres KC, Ribeiro RP, Colle D, dos Santos AA, Moreira EL et al (2012) Probucol, a lipid-lowering drug, prevents cognitive and hippocampal synaptic impairments induced by amyloid β peptide in mice. Exp Neurol 233(2):767–775

    Article  CAS  PubMed  Google Scholar 

  71. Krishnamurthy K, Cantillana V, Wang H, Sullivan PM, Kolls BJ, Ge X et al (2020) ApoE mimetic improves pathology and memory in a model of Alzheimer’s disease. Brain Res 1733:146685

    Article  CAS  PubMed  Google Scholar 

  72. Serrano-Pozo A, Das S, Hyman BT (2021) APOE and Alzheimer's disease: advances in genetics, pathophysiology, and therapeutic approaches. The Lancet Neurology 20(1):68–80

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Miranda A, Montiel E, Ulrich H, Paz C (2021) Selective secretase targeting for Alzheimer’s disease therapy. J Alzheimers Dis 81(1):1–17

    Article  CAS  PubMed  Google Scholar 

  74. Panza F, Lozupone M, Watling M, Imbimbo BP (2019) Do BACE inhibitor failures in Alzheimer patients challenge the amyloid hypothesis of the disease? Expert Rev Neurother 19(7):599–602

    Article  CAS  PubMed  Google Scholar 

  75. Huang L-K, Chao S-P, Hu C-J (2020) Clinical trials of new drugs for Alzheimer disease. J Biomed Sci 27(1):1–13

    Article  Google Scholar 

  76. Uddin MS, Hossain MF, Al Mamun A, Shah MA, Hasana S, Bulbul IJ et al (2020) Exploring the multimodal role of phytochemicals in the modulation of cellular signaling pathways to combat age-related neurodegeneration. Sci Total Environ 725:138313

    Article  CAS  PubMed  Google Scholar 

  77. Mahase E (2021) Three FDA advisory panel members resign over approval of Alzheimer’s drug. British Medical Journal Publishing Group

    Book  Google Scholar 

  78. Tolar M, Abushakra S, Hey JA, Porsteinsson A, Sabbagh M (2020) Aducanumab, gantenerumab, BAN2401, and ALZ-801—the first wave of amyloid-targeting drugs for Alzheimer’s disease with potential for near term approval. Alzheimers Res Ther 12:1–10

    Article  Google Scholar 

  79. Tanzi RE (2012) The genetics of Alzheimer disease. Cold Spring Harb Perspect Med 2(10):a006296

    Article  PubMed  PubMed Central  Google Scholar 

  80. Wahrle SE, Jiang H, Parsadanian M, Kim J, Li A, Knoten A et al (2008) Overexpression of ABCA1 reduces amyloid deposition in the PDAPP mouse model of Alzheimer disease. J Clin Invest 118(2):671–682

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Wahrle SE, Jiang H, Parsadanian M, Hartman RE, Bales KR, Paul SM et al (2005) Deletion of Abca1 increases Aβ deposition in the PDAPP transgenic mouse model of Alzheimer disease. J Biol Chem 280(52):43236–43242

    Article  CAS  PubMed  Google Scholar 

  82. Champagne D, Pearson D, Dea D, Rochford J, Poirier J (2003) The cholesterol-lowering drug probucol increases apolipoprotein E production in the hippocampus of aged rats: implications for Alzheimer’s disease. Neuroscience 121(1):99–110

    Article  CAS  PubMed  Google Scholar 

  83. Kuszczyk MA, Sanchez S, Pankiewicz J, Kim J, Duszczyk M, Guridi M et al (2013) Blocking the interaction between apolipoprotein E and Aβ reduces intraneuronal accumulation of Aβ and inhibits synaptic degeneration. Am J Pathol 182(5):1750–1768

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Holtzman DM, Fagan AM, Mackey B, Tenkova T, Sartorius L, Paul SM et al (2000) Apolipoprotein E facilitates neuritic and cerebrovascular plaque formation in an Alzheimer's disease model. Ann Neurol 47(6):739–747

    Article  CAS  PubMed  Google Scholar 

  85. Ulrich JD, Ulland TK, Mahan TE, Nyström S, Nilsson KP, Song WM et al (2018) ApoE facilitates the microglial response to amyloid plaque pathology. J Exp Med 215(4):1047–1058

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Kim J, Castellano JM, Jiang H, Basak JM, Parsadanian M, Pham V et al (2009) Overexpression of low-density lipoprotein receptor in the brain markedly inhibits amyloid deposition and increases extracellular Aβ clearance. Neuron 64(5):632–644

    Article  PubMed  PubMed Central  Google Scholar 

  87. Huynh T-PV, Liao F, Francis CM, Robinson GO, Serrano JR, Jiang H et al (2017) Age-dependent effects of apoE reduction using antisense oligonucleotides in a model of β-amyloidosis. Neuron 96(5):1013–23. e4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Lin Y-T, Seo J, Gao F, Feldman HM, Wen H-L, Penney J et al (2018) APOE4 causes widespread molecular and cellular alterations associated with Alzheimer’s disease phenotypes in human iPSC-derived brain cell types. Neuron 98(6):1141–54.e7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Hudry E, Dashkoff J, Roe AD, Takeda S, Koffie RM, Hashimoto T et al (2013) Gene transfer of human Apoe isoforms results in differential modulation of amyloid deposition and neurotoxicity in mouse brain. Sci Transl Med 5(212):212ra161

    Article  PubMed  PubMed Central  Google Scholar 

  90. Soeda Y, Takashima A (2020) New insights into drug discovery targeting tau protein. Front Mol Neurosci 13:590896

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Chandrasegaran S, Carroll D (2016) Origins of programmable nucleases for genome engineering. J Mol Biol 428(5):963–989

    Article  CAS  PubMed  Google Scholar 

  92. Doudna JA, Charpentier E (2014) The new frontier of genome engineering with CRISPR-Cas9. Science 346(6213):1258096

    Article  PubMed  Google Scholar 

  93. Hu JH, Davis KM, Liu DR (2016) Chemical biology approaches to genome editing: understanding, controlling, and delivering programmable nucleases. Cell Chem Biol 23(1):57–73

    Article  CAS  PubMed  Google Scholar 

  94. Hsu PD, Lander ES, Zhang F (2014) Development and applications of CRISPR-Cas9 for genome engineering. Cell 157(6):1262–1278

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Cong L, Ran FA, Cox D, Lin S, Barretto R, Habib N et al (2013) Multiplex genome engineering using CRISPR/Cas systems. Science 339(6121):819–823

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Yin H, Xue W, Chen S, Bogorad RL, Benedetti E, Grompe M et al (2014) Genome editing with Cas9 in adult mice corrects a disease mutation and phenotype. Nat Biotechnol 32(6):551–553

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Liang P, Xu Y, Zhang X, Ding C, Huang R, Zhang Z et al (2015) CRISPR/Cas9-mediated gene editing in human tripronuclear zygotes. Protein Cell 6(5):363–372

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Schwank G, Koo B-K, Sasselli V, Dekkers JF, Heo I, Demircan T et al (2013) Functional repair of CFTR by CRISPR/Cas9 in intestinal stem cell organoids of cystic fibrosis patients. Cell Stem Cell 13(6):653–658

    Article  CAS  PubMed  Google Scholar 

  99. Tabebordbar M, Zhu K, Cheng JK, Chew WL, Widrick JJ, Yan WX et al (2016) In vivo gene editing in dystrophic mouse muscle and muscle stem cells. Science 351(6271):407–411

    Article  CAS  PubMed  Google Scholar 

  100. Nelson CE, Hakim CH, Ousterout DG, Thakore PI, Moreb EA, Rivera RMC et al (2016) In vivo genome editing improves muscle function in a mouse model of Duchenne muscular dystrophy. Science 351(6271):403–407

    Article  CAS  PubMed  Google Scholar 

  101. Long C, McAnally JR, Shelton JM, Mireault AA, Bassel-Duby R, Olson EN (2014) Prevention of muscular dystrophy in mice by CRISPR/Cas9–mediated editing of germline DNA. Science 345(6201):1184–1188

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Wojtal D, Kemaladewi DU, Malam Z, Abdullah S, Wong TW, Hyatt E et al (2016) Spell checking nature: versatility of CRISPR/Cas9 for developing treatments for inherited disorders. Am J Hum Genet 98(1):90–101

    Article  CAS  PubMed  Google Scholar 

  103. Canver MC, Smith EC, Sher F, Pinello L, Sanjana NE, Shalem O et al (2015) BCL11A enhancer dissection by Cas9-mediated in situ saturating mutagenesis. Nature 527(7577):192–197

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Rabinowitz R, Kadair A, Ben-Zur T, Michaelson D, Offen D (2019) ApoE4 allele specific knockout using a synthetic Cas9 variant as a potential gene therapy approach for Alzheimer's disease. Cytotherapy 21(5):e7

    Article  Google Scholar 

  105. Sharma G, Sharma AR, Bhattacharya M, Lee SS, Chakraborty C (2021) CRISPR-Cas9: a preclinical and clinical perspective for the treatment of human diseases. Mol Ther 29(2):571–586

    Article  CAS  PubMed  Google Scholar 

  106. Heler R, Samai P, Modell JW, Weiner C, Goldberg GW, Bikard D et al (2015) Cas9 specifies functional viral targets during CRISPR-Cas adaptation. Nature 519(7542):199–202

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Szczelkun MD, Tikhomirova MS, Sinkunas T, Gasiunas G, Karvelis T, Pschera P et al (2014) Direct observation of R-loop formation by single RNA-guided Cas9 and cascade effector complexes. Proc Natl Acad Sci USA 111(27):9798–9803

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Sternberg SH, Redding S, Jinek M, Greene EC, Doudna JA (2014) DNA interrogation by the CRISPR RNA-guided endonuclease Cas9. Nature 507(7490):62–67

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Deltcheva E, Chylinski K, Sharma CM, Gonzales K, Chao Y, Pirzada ZA et al (2011) CRISPR RNA maturation by trans-encoded small RNA and host factor RNase III. Nature 471(7340):602–607

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Gasiunas G, Barrangou R, Horvath P, Siksnys V (2012) Cas9-crRNA ribonucleoprotein complex mediates specific DNA cleavage for adaptive immunity in bacteria. Proc Natl Acad Sci USA 109(39):E2579–E2586

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Jinek M, Chylinski K, Fonfara I, Hauer M, Doudna JA, Charpentier E (2012) A programmable dual-RNA-guided DNA endonuclease in adaptive bacterial immunity. Science 337(6096):816–821

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Barrangou R, Horvath P (2017) A decade of discovery: CRISPR functions and applications. Nat Microbiol 2:17092

    Article  CAS  PubMed  Google Scholar 

  113. Qi LS, Larson MH, Gilbert LA, Doudna JA, Weissman JS, Arkin AP et al (2021) Repurposing CRISPR as an RNA-guided platform for sequence-specific control of gene expression. Cell 184(3):844

    Article  CAS  PubMed  Google Scholar 

  114. Anton T, Karg E, Bultmann S (2018) Applications of the CRISPR/Cas system beyond gene editing. Biol Methods Protoc 3(1):bpy002

    Article  PubMed  PubMed Central  Google Scholar 

  115. Heidenreich M, Zhang F (2016) Applications of CRISPR-Cas systems in neuroscience. Nat Rev Neurosci 17(1):36–44

    Article  CAS  PubMed  Google Scholar 

  116. Ran FA, Hsu PD, Lin CY, Gootenberg JS, Konermann S, Trevino AE et al (2013) Double nicking by RNA-guided CRISPR Cas9 for enhanced genome editing specificity. Cell 154(6):1380–1389

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Zheng Y, Li J, Wang B, Han J, Hao Y, Wang S et al (2020) Endogenous type I CRISPR-Cas: from foreign DNA defense to prokaryotic engineering. Front Bioeng Biotechnol 8:62

    Article  PubMed  PubMed Central  Google Scholar 

  118. Doudna JA, Gersbach CA (2015) Genome editing: the end of the beginning. Genome Biol 16:292

    Article  PubMed  PubMed Central  Google Scholar 

  119. Cox DB, Platt RJ, Zhang F (2015) Therapeutic genome editing: prospects and challenges. Nat Med 21(2):121–131

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Liu C, Zhang L, Liu H, Cheng K (2017) Delivery strategies of the CRISPR-Cas9 gene-editing system for therapeutic applications. J Control Release 266:17–26

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Wu Z, Yang H, Colosi P (2010) Effect of genome size on AAV vector packaging. Mol Ther 18(1):80–86

    Article  CAS  PubMed  Google Scholar 

  122. Sander JD, Joung JK (2014) CRISPR-Cas systems for editing, regulating and targeting genomes. Nat Biotechnol 32(4):347–355

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Tsai SQ, Joung JK (2016) Defining and improving the genome-wide specificities of CRISPR-Cas9 nucleases. Nat Rev Genet 17(5):300–312

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Kuscu C, Arslan S, Singh R, Thorpe J, Adli M (2014) Genome-wide analysis reveals characteristics of off-target sites bound by the Cas9 endonuclease. Nat Biotechnol 32(7):677–683

    Article  CAS  PubMed  Google Scholar 

  125. Zhang XH, Tee LY, Wang XG, Huang QS, Yang SH (2015) Off-target effects in CRISPR/Cas9-mediated genome engineering. Mol Ther Nucleic Acids 4(11):e264

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Haeussler M, Schönig K, Eckert H, Eschstruth A, Mianné J, Renaud JB et al (2016) Evaluation of off-target and on-target scoring algorithms and integration into the guide RNA selection tool CRISPOR. Genome Biol 17(1):148

    Article  PubMed  PubMed Central  Google Scholar 

  127. Lanphier E, Urnov F, Haecker SE, Werner M, Smolenski J (2015) Don’t edit the human germ line. Nature 519(7544):410–411

    Article  CAS  PubMed  Google Scholar 

  128. Isasi R, Kleiderman E, Knoppers BM (2016) Genetic technology regulation. Editing policy to fit the genome? Science 351(6271):337–339

    Article  CAS  PubMed  Google Scholar 

  129. De Plano LM, Calabrese G, Conoci S, Guglielmino SPP, Oddo S, Caccamo A (2022) Applications of CRISPR-Cas9 in Alzheimer's disease and related disorders. Int J Mol Sci 23(15):8714

    Article  PubMed  PubMed Central  Google Scholar 

  130. Lu L, Yu X, Cai Y, Sun M, Yang H (2021) Application of CRISPR/Cas9 in Alzheimer's disease. Front Neurosci 15:803894

    Article  PubMed  PubMed Central  Google Scholar 

  131. Querfurth HW, LaFerla FM (2010) Alzheimer's disease. N Engl J Med 362(4):329–344

    Article  CAS  PubMed  Google Scholar 

  132. Bhardwaj S, Kesari KK, Rachamalla M, Mani S, Ashraf GM, Jha SK et al (2022) CRISPR/Cas9 gene editing: new hope for Alzheimer's disease therapeutics. J Adv Res 40:207–221

    Article  CAS  PubMed  Google Scholar 

  133. Bettens K, Sleegers K, Van Broeckhoven C (2013) Genetic insights in Alzheimer's disease. Lancet Neurol 12(1):92–104

    Article  CAS  PubMed  Google Scholar 

  134. Tcw J, Goate AM (2017) Genetics of beta-amyloid precursor protein in Alzheimer's disease. Cold Spring Harb Perspect Med 7(6):a024539

    Article  PubMed  PubMed Central  Google Scholar 

  135. Bae B, Miura P (2020) Emerging roles for 3' UTRs in neurons. Int J Mol Sci 21(10):3413

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Schuster SL, Hsieh AC (2019) The untranslated regions of mRNAs in cancer. Trends Cancer 5(4):245–262

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Chatterjee S, Pal JK (2009) Role of 5'- and 3'-untranslated regions of mRNAs in human diseases. Biol Cell 101(5):251–262

    Article  CAS  PubMed  Google Scholar 

  138. Galvan V, Gorostiza OF, Banwait S, Ataie M, Logvinova AV, Sitaraman S et al (2006) Reversal of Alzheimer's-like pathology and behavior in human APP transgenic mice by mutation of Asp664. Proc Natl Acad Sci USA 103(18):7130–7135

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Nagata K, Takahashi M, Matsuba Y, Okuyama-Uchimura F, Sato K, Hashimoto S et al (2018) Generation of App knock-in mice reveals deletion mutations protective against Alzheimer's disease-like pathology. Nat Commun 9(1):1800

    Article  PubMed  PubMed Central  Google Scholar 

  140. Mullan M, Crawford F, Axelman K, Houlden H, Lilius L, Winblad B et al (1992) A pathogenic mutation for probable Alzheimer's disease in the APP gene at the N-terminus of beta-amyloid. Nat Genet 1(5):345–347

    Article  CAS  PubMed  Google Scholar 

  141. Gyorgy B, Loov C, Zaborowski MP, Takeda S, Kleinstiver BP, Commins C et al (2018) CRISPR/Cas9 mediated disruption of the Swedish APP allele as a therapeutic approach for early-onset Alzheimer's disease. Mol Ther Nucleic Acids 11:429–440

    Article  PubMed  PubMed Central  Google Scholar 

  142. Sims R, van der Lee SJ, Naj AC, Bellenguez C, Badarinarayan N, Jakobsdottir J et al (2017) Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease. Nat Genet 49(9):1373–1384

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Takalo M, Wittrahm R, Wefers B, Parhizkar S, Jokivarsi K, Kuulasmaa T et al (2020) The Alzheimer's disease-associated protective Plcgamma2-P522R variant promotes immune functions. Mol Neurodegener 15(1):52

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Yang A, Kantor B, Chiba-Falek O (2021) APOE: the new frontier in the development of a therapeutic target towards precision medicine in late-onset Alzheimer's. Int J Mol Sci 22(3):1244

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Wang C, Najm R, Xu Q, Jeong DE, Walker D, Balestra ME et al (2018) Gain of toxic apolipoprotein E4 effects in human iPSC-derived neurons is ameliorated by a small-molecule structure corrector. Nat Med 24(5):647–657

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Liu CC, Liu CC, Kanekiyo T, Xu H, Bu G (2013) Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy. Nat Rev Neurol 9(2):106–118

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. de Almada BV, de Almeida LD, Camporez D, de Moraes MV, Morelato RL, Perrone AM et al (2012) Protective effect of the APOE-e3 allele in Alzheimer's disease. Braz J Med Biol Res 45(1):8–12

    Article  PubMed  Google Scholar 

  148. Delabio R, Rasmussen L, Mizumoto I, Viani GA, Chen E, Villares J et al (2014) PSEN1 and PSEN2 gene expression in Alzheimer's disease brain: a new approach. J Alzheimers Dis 42(3):757–760

    Article  CAS  PubMed  Google Scholar 

  149. Ortiz-Virumbrales M, Moreno CL, Kruglikov I, Marazuela P, Sproul A, Jacob S et al (2017) CRISPR/Cas9-Correctable mutation-related molecular and physiological phenotypes in iPSC-derived Alzheimer's PSEN2 (N141I) neurons. Acta Neuropathol Commun 5(1):77

    Article  PubMed  PubMed Central  Google Scholar 

  150. Yan R, Vassar R (2014) Targeting the beta secretase BACE1 for Alzheimer's disease therapy. Lancet Neurol 13(3):319–329

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Park H, Oh J, Shim G, Cho B, Chang Y, Kim S et al (2019) In vivo neuronal gene editing via CRISPR-Cas9 amphiphilic nanocomplexes alleviates deficits in mouse models of Alzheimer's disease. Nat Neurosci 22(4):524–528

    Article  CAS  PubMed  Google Scholar 

  152. He G, Luo W, Li P, Remmers C, Netzer WJ, Hendrick J et al (2010) Gamma-secretase activating protein is a therapeutic target for Alzheimer's disease. Nature 467(7311):95–98

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Wong E, Liao GP, Chang JC, Xu P, Li YM, Greengard P (2019) GSAP modulates gamma-secretase specificity by inducing conformational change in PS1. Proc Natl Acad Sci USA 116(13):6385–6390

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Lee JK, Kim NJ (2017) Recent advances in the inhibition of p38 MAPK as a potential strategy for the treatment of Alzheimer's disease. Molecules 22(8):1287

    Article  PubMed  PubMed Central  Google Scholar 

  155. Raikwar SP, Thangavel R, Dubova I, Selvakumar GP, Ahmed ME, Kempuraj D et al (2019) Targeted gene editing of glia maturation factor in microglia: a novel Alzheimer's disease therapeutic target. Mol Neurobiol 56(1):378–393

    Article  CAS  PubMed  Google Scholar 

  156. Barman NC, Khan NM, Islam M, Nain Z, Roy RK, Haque A et al (2020) CRISPR-Cas9: a promising genome editing therapeutic tool for Alzheimer's disease-a narrative review. Neurol Ther 9(2):419–434

    Article  PubMed  PubMed Central  Google Scholar 

  157. Sun J, Carlson-Stevermer J, Das U, Shen M, Delenclos M, Snead AM et al (2019) CRISPR/Cas9 editing of APP C-terminus attenuates beta-cleavage and promotes alpha-cleavage. Nat Commun 10(1):53

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Perutz MF, Johnson T, Suzuki M, Finch JT (1994) Glutamine repeats as polar zippers: their possible role in inherited neurodegenerative diseases. Proc Natl Acad Sci USA 91(12):5355–5358

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Konermann S, Brigham MD, Trevino AE, Joung J, Abudayyeh OO, Barcena C et al (2015) Genome-scale transcriptional activation by an engineered CRISPR-Cas9 complex. Nature 517(7536):583–588

    Article  CAS  PubMed  Google Scholar 

  160. Park H, Hwang Y, Kim J (2021) Transcriptional activation with Cas9 activator nanocomplexes rescues Alzheimer's disease pathology. Biomaterials 279:121229

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors thank the Department of Biochemistry and the Faculty of Medicine for all support provided. Also, we would like to appreciate BioRender.com for providing valuable visualization tools and templates. We have used several BioRender templates, including the CRISPR-Cas9 system template, which has remarkably enhanced the impact of our paper.

Author information

Authors and Affiliations

  1. Cellular and Molecular Research Center, Cellular and Molecular Medicine Institute, Urmia University of Medical Sciences, Urmia, Iran

    Shahriar Alipour

  2. Department of Clinical Biochemistry, Faculty of Medicine, Urmia University Medical Sciences (UMSU), Urmia, Iran

    Sepideh Hassani & Shahriar Alipour

  3. Department of Clinical Biochemistry and Applied Cell Sciences, Faculty of Medicine, Urmia University of Medical Sciences, Urmia, Iran

    Shahriar Alipour

  4. Student Research Committee, Urmia University of Medical Sciences, Urmia, Iran

    Araz Rahimi, Parsa Sameei, Sana Mousavi, Kimia Ghaderi, Amin Hassani, Sepideh Hassani & Shahriar Alipour

Authors
  1. Araz Rahimi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Parsa Sameei
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Sana Mousavi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Kimia Ghaderi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Amin Hassani
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Sepideh Hassani
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Shahriar Alipour
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Rahimi A. and Alipour Sh. designed the investigation, Alipour Sh. and Hassani S. divided each author’s responsibilities, Sameei P. and Hassani A. prepared the figures and revised the work, Moosavi S. and Ghaderi K. managed the article writing and submission, Hassani S. and Hassani A. worked on language editing.

Corresponding authors

Correspondence to Sepideh Hassani or Shahriar Alipour.

Ethics declarations

Ethical Approval

This article is a review and does not need to receive the code of ethics

Conflict of Interest

The authors declare no competing interests.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

ESM 1

(PDF 7144 kb)

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Rahimi, A., Sameei, P., Mousavi, S. et al. Application of CRISPR/Cas9 System in the Treatment of Alzheimer’s Disease and Neurodegenerative Diseases. Mol Neurobiol (2024). https://doi.org/10.1007/s12035-024-04143-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s12035-024-04143-2

Keywords

Search

Navigation