Application of CRISPR/Cas9 in Alzheimer’s Disease

Abstract

Alzheimer’s disease (AD) is a progressive and irreversible neurodegenerative disorder clinically characterized by cognitive impairment, abnormal behavior, and social deficits, which is intimately linked with excessive β-amyloid (Aβ) protein deposition along with many other misfolded proteins, neurofibrillary tangles formed by hyperphosphorylated tau protein aggregates, and mitochondrial damage in neurons, leading to neuron loss. Currently, research on the pathological mechanism of AD has been elucidated for decades, still no effective treatment for this complex disease was developed, and the existing therapeutic strategies are extremely erratic, thereby leading to irreversible and progressive cognitive decline in AD patients. Due to gradually mental dyscapacitating of AD patients, AD not only brings serious physical and psychological suffering to patients themselves, but also imposes huge economic burdens on family and society. Accordingly, it is very imperative to recapitulate the progress of gene editing-based precision medicine in the emerging fields. In this review, we will mainly focus on the application of CRISPR/Cas9 technique in the fields of AD research and gene therapy, and summarize the application of CRISPR/Cas9 in the aspects of AD model construction, screening of pathogenic genes, and target therapy. Finally, the development of delivery systems, which is a major challenge that hinders the clinical application of CRISPR/Cas9 technology will also be discussed.

An Update on the Application of CRISPR Technology in Clinical Practice

“…Accumulation of amyloid-beta (Aβ) and tau proteins are related to alzheimer’s disease—AD pathophysiology. Since many genetic factors such as oxidative stress, vascular dysfunction, proteinopathy, metal ions, inflammation, mitochondrial dysfunction, lipid metabolism, microbiota–gut–brain axis, and gene-environment interactions are associated with the pathophysiology of AD [ 125 ], various studies proposed either knocking out APP, PSEN1, PSEN2, CysLT1R, GMF, BACE1, Th genes [ 120 – 123 ] or correcting APOE4 alleles to E3 or E2 as a potential treatment approach for AD [ 121 , 124 ]. Various CRISPR/Cas systems were used as powerful techniques to reach this goal.…”

Applications of CRISPR-Cas9 in Alzheimer’s Disease and Related Disorders

“…These models have proven to be extremely useful for understanding some aspects of AD pathogenesis, but their utility is limited because most of the AD mouse models do not develop frank neurodegeneration [ 45 ]. Recently, CRISPR-Cas9 technology has been used to create new AD models that show a more accurate disease phenotype, elucidate mechanisms of pathogenesis, screen pathogenic genes, and at the same time, find a therapy for this insidious disorder [ 46 ]. We, briefly, described below the most significant examples.…”

New Therapeutics for Extracellular Vesicles: Delivering CRISPR for Cancer Treatment

“…In contrast, the class 2 system, including types II, V, and VI, has an endonuclease module with a single-protein effector, which is more feasible for engineering [ 21 , 32 , 33 ]. Specifically, Cas9, as a single-chain endonuclease in the type II system, has been extensively studied to expand the genome toolkit [ 25 , 34 ].…”