CRISPR/Cas9 gene editing: New hope for Alzheimer's disease therapeutics

Abstract

Background: Alzheimer's disease (AD) is an insidious, irreversible, and progressive neurodegenerative health condition manifesting as cognitive deficits and amyloid beta (Aβ) plaques and neurofibrillary tangles. Approximately 50 million individuals are affected by AD, and the number is rapidly increasing globally. This review explores the role of CRISPR/Cas9 gene editing in the management of AD and its clinical manifestations.

Aim of review: This review aims to provide a deep insight into the recent progress in CRISPR/Cas9-mediated genome editing and its use against neurodegenerative disorders, specifically AD. However, we have referred to its use against parkinsons's disease (PD), Huntington's disease (HD), and other human diseases, as is one of the most promising and emerging technologies for disease treatment.

Key scientific concepts of review: The pathophysiology of AD is known to be linked with gene mutations, that is, presenilin (PSEN) and amyloid beta precursor protein (APP). However, clinical trials focused at the genetic level could not meet the desired efficiency. The CRISPR/Cas9 genome editing tool is one of the most powerful technologies for correcting inconsistent genetic signatures and now extensively used for AD management. It has significant potential for the correction of undesired gene mutations associated with AD. This technology has allowed the development of empirical AD models, therapeutic lines, and diagnostic approaches for better understanding the nervous system, from in vitro to in vivo models.

Keywords: APP; Alzheimer’s disease; CRISPR/Cas9; Gene editing; Neurodegeneration; Presenilin; Therapeutics.

Graphical abstract

Fig. 1

Schematic showing Amyloid beta and Tau hypothesis that have been suggested to give an explanation for the most common characteristic hallmarks of AD. APP, amyloid precursor protein; AICD, APP intracellular domain; NFTs, neurofibrillary tangles; GSK, glycogen synthase kinase; CDK5, cyclin-dependent kinase 5; PP2A, protein phosphatase 2A.

Fig. 2

The CRISPR/Cas9 timeline, crRNA: CRISPR-derived RNA; CRISPR/Cas9, clustered regularly interspaced short palindromic repeats/CRISPR-associated proteins 9 system.

Fig. 3

A schematic cartoon illustrating the steps involved in CRISPR/Cas9 technique. (A) Specially designed sgRNA (guide RNA) which matches with genomic DNA sequence containing mutation, attaches with Cas9 (CRISPR-associated endonuclease), a DNAase capable of inducing a double strand break, thereby, forming Cas9-sgRNA complex. (B) Association of Cas9-sgRNA complex with the target genomic DNA. Cas9 searches for appropriate sequence in target DNA with the help of sgRNA and recognises it with the help of PAMs (protospacer adjacent motifs) sequence, usually 2–6 base pair long, found 3–4 nucleotide downstream from cut site generally serve as a tag. (C) Cas9 mediated DNA cleavage leads to the formation of double strand break (DSB). (D) Formation of DSB leads to the activation of DNA repair mechanism to correct the break by sealing the gap either by Non-Homologous End Joining (NHEJ) or Homology Directed Repair (HDR).

Fig. 4

Illustration showing the possible CRISPR/Cas9 mediated gene editing approach in AD. GWAS, genome-wide association studies.

Fig. 5

The diverse applications of CRISPR/Cas9 technique in human diseases. Here in this schematic, we have highlighted the disease associated various genes and proteins which may be one of the possible target for this gene editing strategy. MYBPC3, myosin binding protein C3; BRAF, B-Raf proto-oncogene, serine/threonine kinase; PTEN, phosphatase and tensin homolog; EGFR, epidermal growth factor receptor; HER2, human epidermal growth factor receptor 2; CASP8, caspase-8; CDKN2A, cyclin-dependent kinase inhibitor 2A; SLC10A1, solute carrier family 10 member 1; TRPC1, canonical transient receptor potential; PINK1, PTEN-induced putative kinase 1; LRRK2, leucine rich repeat kinase 2; SNCA, α-synuclein; mHTT, mutant huntingtin protein; DJ-1, PARK7; DNMT3A, DNA methyltransferase 3a; FBN1, fibrillin-1; PCSK9, proprotein convertase subtilisin/kexin type 9; PLN, phospholamban; PRKAG2, kinase AMP-activated noncatalytic subunit-2; ASPH, aspartate beta-hydroxylase; KRAS, kirsten rat sarcoma viral oncogene homolog; APC, adenomatous polyposis coli; p53, tumor suppressor gene; FEN1, flap endonuclease 1; TET2, epigenetic modifier enzyme; NCOA5, nuclear receptor coactivator 5; Y347X, nonsense point mutation; Reep6, receptor expression-enhancing protein 6; Rp9, pre-mRNA splicing factor; Alb, albumin; Fah, fumarylacetoacetate hydrolase; Otc, Ornithine transcarbamylase; POLK, DNA Polymerase Kappa.