Genome-editing applications of CRISPR–Cas9 to promote in vitro studies of Alzheimer’s disease

Abstract

Genetic variations play an important role in the clinical presentation and progression of Alzheimer’s disease (AD), especially early-onset Alzheimer’s disease. Hundreds of mutations have been reported with the majority resulting from alterations in β-amyloid precursor protein (APP), presenilin 1 (PSEN1), or presenilin 2 (PSEN2) genes. The roles of these mutations in the pathogenesis of AD have been classically confirmed or refuted through functional studies, where the mutations are cloned, inserted into cell lines, and monitored for changes in various properties including cell survival, amyloid production, or Aβ42/40 ratio. However, these verification studies tend to be expensive, time consuming, and inconsistent. Recently, the clustered regularly interspaced short palindromic repeats-CRISPR-associated protein 9 (CRISPR–Cas9) system was developed, which improves sequence-specific gene editing in cell lines, organs, and animals. CRISPR–Cas9 is a promising tool for the generation of models of human genetic diseases and could facilitate the establishment of new animal AD models and the observation of dynamic bioprocesses in AD. Here, we recapitulated the history of CRISPR technology, recent progress, and, especially, its potential applications in AD-related genetic, animal modeling, and functional studies.

Thiamine deficiency contributes to synapse and neural circuit defects

“…Apolipoprotein E ε4 (APOE 4), β-amyloid precursor protein (APP), presenilin 1 (PSEN1), or presenilin 2 (PSEN2) genes have been well reported in the pathogenesis of AD. Genome-editing applications such as CRISPR–Cas9 and induced pluripotent stem cell (iPSc) have been used in remodeling AD genetic mutations and disease progression [ 12 , 13 ]. It is not surprising that synaptic dysfunction can be hardly found in such models, since neuronal maturation is one of the biggest challenges for researcher to overcome [ 14 ].…”

Identification of a novel mutation in <em>APP</em> gene in a Thai subject with early-onset Alzheimer&#39;s disease

“…Approximately, 25 APP mutations were reported as pathogenic variants among 32 coding mutations in APP gene, and several of them presented in autosomal dominant pattern of EOAD. 6 , 15 Overproductions of total Aβ or changes in the Aβ1–40:Aβ1–42 ratio toward formation of more toxic Aβ1–42 peptide were the results from the variants at or near the β- and γ-proteolytic sites. 16 On the other hand, the variants within the region of Aβ could result in the formation of Aβ oligomers with increased propensity for aggregation.…”

CRISPR-Cas9 Technology, Safety and Evaluation from an Ethical Perspective

“…2016 yılında CRISPR-Cas9 sistemi ilk kez Alzheimer hastalığı mutasyonlarını [amiloid prekürsör protein (APP) İsveç tipi ve Presenilin-1 (PSEN1) M146V mutasyonları ile ko-transfeksiyon] modellemek için kullanılmış ve benzer nörodejeneratif hastalıkların patogenezinin aydınlatılmasıyla ilgili yapılacak çalışmalarda yeni verilerin elde edilmesini kolaylaştırabileceği gösterilmiştir. 47 Ailevi amyotrofik lateral skleroz vakalarında süperoksit dismutaz 1 ve RNA bağlanan protein FUS (Fused in Sarcoma/Translocated in Sarcoma, sarkomada füze olmuş/sarkomada transloke olmuş) dâhil birçok gende mutasyonlar bulunmaktadır. CRISPR-Cas9 kullanılarak, SOD A272C ve FUS G1566A gibi patojenik allellerin, indüklenmiş pluripotent kök hücreler (iPSC'ler)'de patojenik olmayan normal allellere dönüştürülebildiği bildirilmiştir.…”